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  1. Th1 and Th2 cytokine responses to academic stress.

    Science.gov (United States)

    Kang, D H; Fox, C

    2001-08-01

    Predominant Th2 profiles are associated with the worsening of asthma, and stress is speculated to induce a Th2 profile. The goals of this study were to examine the responses of the cytokines Th1 (IFN-gamma and IL-2) and Th2 (IL-4, IL-5, and IL-6) to a stressor and to look at the relationships between cytokine and psychological responses. Twenty-four students with and without a history of asthma completed questionnaires and gave blood samples during nonexam and exam periods. Cytokines were measured by ELISA from supernatants of stimulated mononuclear cells (MNC) and whole blood. During examinations, there were a significant decrease in IL-2 and a significant increase in IL-6 production (both cultures) and a significant decrease in IFN-gamma production (MNC cultures). Baseline IL-2 levels showed significant negative correlations with several stress and mood scores. Findings of this study indicate a down-regulation of Th1 and a selective up-regulation of Th2 cytokines during a stressful exposure. Copyright 2001 John Wiley & Sons, Inc.

  2. Competition for antigen between Th1 and Th2 responses determines the timing of the immune response switch during Mycobaterium avium subspecies paratuberulosis infection in ruminants.

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    Gesham Magombedze

    2014-01-01

    Full Text Available Johne's disease (JD, a persistent and slow progressing infection of ruminants such as cows and sheep, is caused by slow replicating bacilli Mycobacterium avium subspecies paratuberculosis (MAP infecting macrophages in the gut. Infected animals initially mount a cell-mediated CD4 T cell response against MAP which is characterized by the production of interferon gamma (Th1 response. Over time, Th1 response diminishes in most animals and antibody response to MAP antigens becomes dominant (Th2 response. The switch from Th1 to Th2 response occurs concomitantly with disease progression and shedding of the bacteria in feces. Mechanisms controlling this Th1/Th2 switch remain poorly understood. Because Th1 and Th2 responses are known to cross-inhibit each other, it is unclear why initially strong Th1 response is lost over time. Using a novel mathematical model of the immune response to MAP infection we show that the ability of extracellular bacteria to persist outside of macrophages naturally leads to switch of the cellular response to antibody production. Several additional mechanisms may also contribute to the timing of the Th1/Th2 switch including the rate of proliferation of Th1/Th2 responses at the site of infection, efficiency at which immune responses cross-inhibit each other, and the rate at which Th1 response becomes exhausted over time. Our basic model reasonably well explains four different kinetic patterns of the Th1/Th2 responses in MAP-infected sheep by variability in the initial bacterial dose and the efficiency of the MAP-specific T cell responses. Taken together, our novel mathematical model identifies factors of bacterial and host origin that drive kinetics of the immune response to MAP and provides the basis for testing the impact of vaccination or early treatment on the duration of infection.

  3. The inflammasome drives protective Th1 and Th17 cellular responses in disseminated candidiasis

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    van de Veerdonk, Frank L.; Joosten, Leo A.B.; Shaw, Patrick J.; Smeekens, Sanne P.; Malireddi, Subbarao; van der Meer, Jos W.M.; Kullberg, Bart-Jan; Netea, Mihai G.; Kanneganti, Thirumala-Devi

    2014-01-01

    The Nlrp3 inflammasome has been proposed to play an important role in antifungal host defense. However, studies exploring the role of the inflammasome in antifungal host defense have been limited to the direct effects on IL-1β processing. Although IL-1β has important direct effects on the innate immune response, important effects of the caspase-1-dependent cytokines IL-1β and IL-18 are exerted on the initiation of adaptive cellular responses Th1 and Th17. No studies have been employed to assess the impact of the inflammasome on the Th1/Th17 defense mechanisms in-vivo during candidiasis. In the present study we demonstrate an essential role for caspase-1 and ASC in disseminated candidiasis through regulating antifungal Th1 and Th17 responses. Caspase-1−/− and ASC−/− mice display diminished Th1/Th17 responses, followed by increased fungal outgrowth and lower survival. These observations identify a critical role for the inflammasome in controlling protective adaptive immune responses during invasive fungal infection. PMID:21681738

  4. Academic stress-induced changes in Th1- and Th2-cytokine response

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    Areej M. Assaf

    2017-12-01

    Full Text Available Psychological stress stimulates physiological responses releasing catecholamines and corticoids, which act via corresponding receptors on immune cells, producing a shift in the cytokine balance. These responses are variable depending on the nature of stressors. The effect of the academic stress on the production of the Th1-cytokines (TNF-α, IFN-γ, IL-1β, IL-2, IL-6 and IL-8 and Th2-cytokines (IL-1ra, IL-4, IL-5 and IL-10 on 35 medical/health sciences students after completing their questionnaires was investigated. Blood samples were taken at three stages; baseline stage at the beginning, midterm and final academic examination stages. Plasma cortisol and cytokines were measured during the three stages. The last two stages were compared with the baseline non-stress period. Results of the stress induced during the final examination stage were the highest with a significant increase in cortisol release, IL-4, IL-5 and IL-1ra release with a shift in Th1:Th2 cytokines balance towards Th2. Whereby, the midterm stage did not show significant reduction in Th1-cytokines except for TNF-α, with an increase in IFN-γ level that was reduced in the third stage. Th2 cytokine, IL-1ra, had positive correlations with Th1 cytokines; IL-2 and IFN-γ in the second stage and IL-6 cytokine in the third stage. Cortisol was positively correlated with IL-8 in the last stage and heart rates had negative correlation with IL-10 in the first and last stages. Findings of this study indicate that exam stress down-regulates Th1 with a selective up-regulation of Th2-cytokines. In conclusion, Cortisol might have a role in suppressing the release of Th1- mediated cellular immune response which could increase the vulnerability among the students to infectious diseases.

  5. Academic stress-induced changes in Th1- and Th2-cytokine response.

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    Assaf, Areej M; Al-Abbassi, Reem; Al-Binni, Maysaa

    2017-12-01

    Psychological stress stimulates physiological responses releasing catecholamines and corticoids, which act via corresponding receptors on immune cells, producing a shift in the cytokine balance. These responses are variable depending on the nature of stressors. The effect of the academic stress on the production of the Th1-cytokines (TNF-α, IFN-γ, IL-1β, IL-2, IL-6 and IL-8) and Th2-cytokines (IL-1ra, IL-4, IL-5 and IL-10) on 35 medical/health sciences students after completing their questionnaires was investigated. Blood samples were taken at three stages; baseline stage at the beginning, midterm and final academic examination stages. Plasma cortisol and cytokines were measured during the three stages. The last two stages were compared with the baseline non-stress period. Results of the stress induced during the final examination stage were the highest with a significant increase in cortisol release, IL-4, IL-5 and IL-1ra release with a shift in Th1:Th2 cytokines balance towards Th2. Whereby, the midterm stage did not show significant reduction in Th1-cytokines except for TNF-α, with an increase in IFN-γ level that was reduced in the third stage. Th2 cytokine, IL-1ra, had positive correlations with Th1 cytokines; IL-2 and IFN-γ in the second stage and IL-6 cytokine in the third stage. Cortisol was positively correlated with IL-8 in the last stage and heart rates had negative correlation with IL-10 in the first and last stages. Findings of this study indicate that exam stress down-regulates Th1 with a selective up-regulation of Th2-cytokines. In conclusion, Cortisol might have a role in suppressing the release of Th1- mediated cellular immune response which could increase the vulnerability among the students to infectious diseases.

  6. Th1-skewed tissue responses to a mycolyl glycolipid in mycobacteria-infected rhesus macaques

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    Morita, Daisuke; Miyamoto, Ayumi; Hattori, Yuki; Komori, Takaya [Laboratory of Cell Regulation, Institute for Virus Research, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Nakamura, Takashi [Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812 (Japan); Igarashi, Tatsuhiko, E-mail: tigarash@virus.kyoto-u.ac.jp [Laboratory of Primate Model, Institute for Virus Research, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Harashima, Hideyoshi, E-mail: harasima@pharm.hokudai.ac.jp [Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812 (Japan); Sugita, Masahiko, E-mail: msugita@virus.kyoto-u.ac.jp [Laboratory of Cell Regulation, Institute for Virus Research, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan)

    2013-11-08

    Highlights: •Glucose monomycolate (GMM) is a marker glycolipid for active tuberculosis. •Tissue responses to GMM involved up-regulation of Th1-attracting chemokines. •Th1-skewed local responses were mounted at the GMM-injected tissue. -- Abstract: Trehalose 6,6′-dimycolate (TDM) is a major glycolipid of the cell wall of mycobacteria with remarkable adjuvant functions. To avoid detection by the host innate immune system, invading mycobacteria down-regulate the expression of TDM by utilizing host-derived glucose as a competitive substrate for their mycolyltransferases; however, this enzymatic reaction results in the concomitant biosynthesis of glucose monomycolate (GMM) which is recognized by the acquired immune system. GMM-specific, CD1-restricted T cell responses have been detected in the peripheral blood of infected human subjects and monkeys as well as in secondary lymphoid organs of small animals, such as guinea pigs and human CD1-transgenic mice. Nevertheless, it remains to be determined how tissues respond at the site where GMM is produced. Here we found that rhesus macaques vaccinated with Mycobacterium bovis bacillus Calmette–Guerin mounted a chemokine response in GMM-challenged skin that was favorable for recruiting T helper (Th)1 T cells. Indeed, the expression of interferon-γ, but not Th2 or Th17 cytokines, was prominent in the GMM-injected tissue. The GMM-elicited tissue response was also associated with the expression of monocyte/macrophage-attracting CC chemokines, such as CCL2, CCL4 and CCL8. Furthermore, the skin response to GMM involved the up-regulated expression of granulysin and perforin. Given that GMM is produced primarily by pathogenic mycobacteria proliferating within the host, the Th1-skewed tissue response to GMM may function efficiently at the site of infection.

  7. Lithocholic acid controls adaptive immune responses by inhibition of Th1 activation through the Vitamin D receptor

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    Puchner, Teresa; Korkmaz, H. Inci; Vos, Mariska; Soeters, Maarten R.; de Vries, Carlie J. M.

    2017-01-01

    Bile acids are established signaling molecules next to their role in the intestinal emulsification and uptake of lipids. We here aimed to identify a potential interaction between bile acids and CD4+ Th cells, which are central in adaptive immune responses. We screened distinct bile acid species for their potency to affect T cell function. Primary human and mouse CD4+ Th cells as well as Jurkat T cells were used to gain insight into the mechanism underlying these effects. We found that unconjugated lithocholic acid (LCA) impedes Th1 activation as measured by i) decreased production of the Th1 cytokines IFNγ and TNFαα, ii) decreased expression of the Th1 genes T-box protein expressed in T cells (T-bet), Stat-1 and Stat4, and iii) decreased STAT1α/β phosphorylation. Importantly, we observed that LCA impairs Th1 activation at physiological relevant concentrations. Profiling of MAPK signaling pathways in Jurkat T cells uncovered an inhibition of ERK-1/2 phosphorylation upon LCA exposure, which could provide an explanation for the impaired Th1 activation. LCA induces these effects via Vitamin D receptor (VDR) signaling since VDR RNA silencing abrogated these effects. These data reveal for the first time that LCA controls adaptive immunity via inhibition of Th1 activation. Many factors influence LCA levels, including bile acid-based drugs and gut microbiota. Our data may suggest that these factors also impact on adaptive immunity via a yet unrecognized LCA-Th cell axis. PMID:28493883

  8. Lithocholic acid controls adaptive immune responses by inhibition of Th1 activation through the Vitamin D receptor.

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    Thijs W H Pols

    Full Text Available Bile acids are established signaling molecules next to their role in the intestinal emulsification and uptake of lipids. We here aimed to identify a potential interaction between bile acids and CD4+ Th cells, which are central in adaptive immune responses. We screened distinct bile acid species for their potency to affect T cell function. Primary human and mouse CD4+ Th cells as well as Jurkat T cells were used to gain insight into the mechanism underlying these effects. We found that unconjugated lithocholic acid (LCA impedes Th1 activation as measured by i decreased production of the Th1 cytokines IFNγ and TNFαα, ii decreased expression of the Th1 genes T-box protein expressed in T cells (T-bet, Stat-1 and Stat4, and iii decreased STAT1α/β phosphorylation. Importantly, we observed that LCA impairs Th1 activation at physiological relevant concentrations. Profiling of MAPK signaling pathways in Jurkat T cells uncovered an inhibition of ERK-1/2 phosphorylation upon LCA exposure, which could provide an explanation for the impaired Th1 activation. LCA induces these effects via Vitamin D receptor (VDR signaling since VDR RNA silencing abrogated these effects. These data reveal for the first time that LCA controls adaptive immunity via inhibition of Th1 activation. Many factors influence LCA levels, including bile acid-based drugs and gut microbiota. Our data may suggest that these factors also impact on adaptive immunity via a yet unrecognized LCA-Th cell axis.

  9. Distinct DC subsets regulate adaptive Th1 and 2 responses during Trichuris muris infection

    DEFF Research Database (Denmark)

    Demiri, M.; Müller-Luda, K.; Agace, William Winston

    2017-01-01

    Low- and high-dose infections with the murine large intestinal nematode Trichuris muris are associated with induction of adaptive Th1 and Th2 responses, respectively, in mesenteric lymph nodes (MLN). Classical dendritic cells (cDC) accumulate in the large intestinal mucosa and MLN upon T. muris...... response and clear a low-dose infection. Collectively, these results suggest that IRF4- and IRF8-dependent cDC act antagonistically during T. muris infection, and demonstrate that intestinal Th2 responses can be generated towards T. muris in the absence of IRF4-dependent cDC....

  10. T-bet-independent Th1 response induces intestinal immunopathology during Toxoplasma gondii infection.

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    López-Yglesias, Américo H; Burger, Elise; Araujo, Alessandra; Martin, Andrew T; Yarovinsky, Felix

    2018-01-03

    Coordinated production of IFN-γ by innate and adaptive immune cells is central for host defense, but can also trigger immunopathology. The investigation of the lymphoid cell-specific contribution to the IFN-γ-mediated intestinal pathology during Toxoplasma gondii infection identified CD4+ T cells as a key cell population responsible for IFN-γ-dependent intestinal inflammation and Paneth cell loss, where T-bet-dependent group 1 innate lymphoid cells have a minor role in driving the parasite-induced immunopathology. This was evident from the analysis of T-bet deficiency that did not prevent the intestinal inflammation and instead revealed that T-bet-deficient CD4+ Th1 cells are sufficient for T. gondii-triggered acute ileitis and Paneth cell loss. These results revealed that T-bet-independent Th1 effector cells are major functional mediators of the type I immunopathological response during acute gastrointestinal infection.Mucosal Immunology advance online publication, 3 January 2018 2017; doi:10.1038/mi.2017.102.

  11. 5-Lipoxygenase negatively regulates Th1 response during Brucella abortus infection in mice.

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    Fahel, Júlia Silveira; de Souza, Mariana Bueno; Gomes, Marco Túlio Ribeiro; Corsetti, Patricia P; Carvalho, Natalia B; Marinho, Fabio A V; de Almeida, Leonardo A; Caliari, Marcelo V; Machado, Fabiana Simão; Oliveira, Sergio Costa

    2015-03-01

    Brucella abortus is a Gram-negative bacterium that infects humans and cattle, causing a chronic inflammatory disease known as brucellosis. A Th1-mediated immune response plays a critical role in host control of this pathogen. Recent findings indicate contrasting roles for lipid mediators in host responses against infections. 5-Lipoxygenase (5-LO) is an enzyme required for the production of the lipid mediators leukotrienes and lipoxins. To determine the involvement of 5-LO in host responses to B. abortus infection, we intraperitoneally infected wild-type and 5-LO-deficient mice and evaluated the progression of infection and concomitant expression of immune mediators. Here, we demonstrate that B. abortus induced the upregulation of 5-LO mRNA in wild-type mice. Moreover, this pathogen upregulated the production of the lipid mediators leukotriene B4 and lipoxin A4 in a 5-LO-dependent manner. 5-LO-deficient mice displayed lower bacterial burdens in the spleen and liver and less severe liver pathology, demonstrating an enhanced resistance to infection. Host resistance paralleled an increased expression of the proinflammatory mediators interleukin-12 (IL-12), gamma interferon (IFN-γ), and inducible nitric oxide synthase (iNOS) during the course of infection. Moreover, we demonstrated that 5-LO downregulated the expression of IL-12 in macrophages during B. abortus infection. Our results suggest that 5-LO has a major involvement in B. abortus infection, by functioning as a negative regulator of the protective Th1 immune responses against this pathogen. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  12. Th1 and Th2 immune responses related to pelvic endometriosis Resposta imunológica Th1 e Th2 relacionada à endometriose pélvica

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    Sergio Podgaec

    2010-01-01

    Full Text Available OBJECTIVE: This study analyzed the relationship between clinical characteristics of endometriosis and Th1/Th2 immune response patterns. METHODS: A prospective study was performed with 65 patients with endometriosis (Group A and 33 without the disease (Group B. Measurement of IL 2, 4 and 10, TNF-alpha and IFN-gamma was carried out in peripheral blood and peritoneal fluid. RESULTS: Serum TNF-alpha was higher in patients with endometriosis who had deep dyspareunia compared to controls (mean 4.5 pg/ml and 2.3 pg/ml, pOBJETIVO: Este estudo analisa a relação entre as características clínicas da endometriose e os padrões da resposta imune Th1/Th2. MÉTODOS: Estudo prospectivo realizado com 65 pacientes com endometriose (Grupo A e 33 pacientes sem a doença (Grupo B. Foram realizadas avaliação no fluido peritoneal e sangue periférico de IL 2, 4 e 10, TNF-alfa e IFN-gama. A significância foi estabelecida em p < 0,05. RESULTADOS: TNF-alfa encontrava-se elevado em pacientes com endometriose que apresentavam dispareunia de profundidade comparado com controle (média 4,5 pg/ml e 2,3 pg/ml, p< 0,05. Dentre essas pacientes (n=32, 65,5% apresentavam endometriose profunda. Pacientes com endometriose e infertilidade apresentavam concentrações maiores de IL-2 no fluido peritoneal quando comparadas com controle (média 5,9 pg/ml e 0,2 pg/ml, p< 0,05, sendo que neste grupo, 63,5% (n=14 apresentavam endometriose profunda. Foi observada também maior concentração de IL-10 nas pacientes que apresentavam endometriose ovariana quando comparadas às sem esse tipo de endometriose, assim como quando comparadas às pacientes do grupo controle (média 50pg/ml, 18,7pg/ml e 25,7pg/ml, p<0,05. CONCLUSÃO: Estes resultados sugerem que quando dados clínicos específicos associam-se a uma produção elevada de certas citocinas, ocorre um padrão de resposta Th1 que pode estar associado à endometriose profunda.

  13. Influence of Probiotic Consortium on TH1 and TH2 Immune Response

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    Gulnara Shakhabayeva

    2014-03-01

    Full Text Available Introduction: The main role of probiotics is to maintain homeostasis in the intestines and improve bowel protective function. The aim of the present study is to investigate immuno-modulatory effects of a probiotic consortium. Methods: Observations were carried out in vitro. The presence of IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ, IgA, IgM, and IgE was studied using a solid-phase enzyme immunosorbent assay on the VECTOR-BEST sets (Russia. Results: Immunomodulatory properties of the probiotic consortium were studied, which consisted of the following strains: Streptococcus thermophilus, Lactococcus lactis, Lactobacillus plantarum, Lactobacillus fermentum, Lactobacillus acidophilus, Bifidobacterium longum, and Bifidobacterium bifidum. Elevated concentrations of INFγ in control samples decreased 3.9 times (p < 0.05 after a saturation of blood with the probiotic consortium. Significant reduction of cytokine levels after the probiotic effects of the consortium was observed in IL-10 by 2.1 times (p < 0.05 and IgA by 1.87 times (p < 0.0005. There was a significant increase in the levels of IL-4, IgE, IL-6, and IL-8 by 1.3 (p < 0.005, 1.1 (p < 0.5, 18.0 (p < 0.005, and 6 (p < 0.05 times, respectively, in comparison with the control samples. IL-4 and INFγ have different effects on the synthesis of IgE. Soluble low affinity receptors FcεRII (CD23 in association with IL-4 facilitate a differentiation of the B-lymphocytes in IgE-synthesizing cells, while γ-INF inhibits this process. It is known that the intracellular expression of γ-INF and IL-4 is the most reliable marker for Th1 and Th2 immune responses, respectively. The conducted studies determined that the ratio of INF-γ/IL-4 was 0.9 (control 4.8, P < 0.005 after the saturation of the blood cells with probiotic consortium. NF-γ/IL4 ratio decreased by 5.3 times compared with a control value, which indicates a reduction in the functional activity of Th1 type lymphocytes in comparison with the

  14. TH1 and TH2 response to Campylobacter jejuni antigen in Guillain-Barre syndrome.

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    Nyati, Kishan K; Prasad, Kashi N; Rizwan, Arshi; Verma, Avantika; Paliwal, Vimal K

    2011-04-01

    To determine the expression of proinflammatory and anti-inflammatory cytokines in lymphocytes from the progressive and recovery phases of Guillain-Barré syndrome (GBS) after stimulation with Campylobacter jejuni outer membrane proteins. Case-control study. Sanjay Gandhi Postgraduate Institute of Medical Sciences. Sixty-five patients with GBS, 60 age- and sex-matched disease control individuals, and 68 healthy control individuals were included in the study. Lymphocytes from patients with GBS were stimulated with C jejuni outer membrane proteins, and the levels of different proinflammatory (T(H)1 [helper T cell, subtype 1]) and anti-inflammatory (T(H)2) cytokines were determined by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. In the progressive phase of the disease, the expressions of interferon γ (IFN-γ), interleukin 1β (IL-1β), tumor necrosis factor (TNF), IL-6, IL-10, and the IFN-γ:IL-4 ratio were significantly upregulated, but expressions of transforming growth factor (TGF)-β1 and IL-4 were lower in patients compared with disease and healthy controls. In contrast, the levels of IFN-γ, IL-1β, TNF, IL-6, IL-10, and the IFN-γ:IL-4 ratio were significantly lower, but TGF-β1 and IL-4 were upregulated in the recovery phase of GBS patients compared with controls. Upregulation of T(H)1 cytokines in the early disease course may be associated with immune-mediated disease progression due to neuronal inflammation, but upregulation of T(H)2 immune response during the later phase aids recovery from the disease.

  15. Specific dietary oligosaccharides increase Th1 responses in a mouse respiratory syncytial virus infection model.

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    Schijf, Marcel A; Kruijsen, Debby; Bastiaans, Jacqueline; Coenjaerts, Frank E J; Garssen, Johan; van Bleek, Grada M; van't Land, Belinda

    2012-11-01

    Breast feeding reduces the risk of developing severe respiratory syncytial virus (RSV) infections in infants. In addition to maternal antibodies, other immune-modulating factors in human milk contribute to this protection. Specific dietary prebiotic oligosaccharides, similar to oligosaccharides present in human milk, were evaluated in a C57BL/6 mouse RSV infection model. During primary RSV infection, increased numbers of RSV-specific CD4(+) T cells producing gamma interferon (IFN-γ) were found in the lungs at days 8 to 10 postinfection in mice receiving diet containing short-chain galactooligosacharides, long-chain fructooligosaccharides, and pectin-derived acidic oligosaccharides (termed scGOS/lcFOS/pAOS). In a Th2-skewed formalin-inactivated (FI)-RSV vaccination model, the prebiotic diet reduced RSV-specific Th2 cytokine (interleukin-4 [IL-4], IL-5, and IL-13)-producing CD4(+) T cells in the lung and the magnitude of airway eosinophilia at day 4 and 6 after infection. This was accompanied by a decreased influx of inflammatory dendritic cells (CD11b(+)/CD11c(+)) and increased numbers of IFN-γ-producing CD4(+) and CD8(+) T cells at day 8 after viral challenge. These findings suggest that specific dietary oligosaccharides can influence trafficking and/or effector functions of innate immune, CD4(+), and CD8(+) T cell subsets in the lungs of RSV-infected mice. In our models, scGOS/lcFOS/pAOS had no effect on weight but increased viral clearance in FI-RSV-vaccinated mice 8 days after infection. The increased systemic Th1 responses potentiated by scGOS/lcFOS/pAOS might contribute to an accelerated Th1/Th2 shift of the neonatal immune system, which might favor protective immunity against viral infections with a high attack rate in early infancy, such as RSV.

  16. Food preservatives sodium benzoate and propionic acid and colorant curcumin suppress Th1-type immune response in vitro.

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    Maier, Elisabeth; Kurz, Katharina; Jenny, Marcel; Schennach, Harald; Ueberall, Florian; Fuchs, Dietmar

    2010-07-01

    Food preservatives sodium benzoate and propionic acid and colorant curcumin are demonstrated to suppress in a dose-dependent manner Th1-type immune response in human peripheral blood mononuclear cells (PBMC) in vitro. Results show an anti-inflammatory property of compounds which however could shift the Th1-Th2-type immune balance towards Th2-type immunity. 2010 Elsevier Ltd. All rights reserved.

  17. Neutrophils exert a suppressive effect on Th1 responses to intracellular pathogen Brucella abortus.

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    Elías Barquero-Calvo

    2013-02-01

    Full Text Available Polymorphonuclear neutrophils (PMNs are the first line of defense against microbial pathogens. In addition to their role in innate immunity, PMNs may also regulate events related to adaptive immunity. To investigate the influence of PMNs in the immune response during chronic bacterial infections, we explored the course of brucellosis in antibody PMN-depleted C57BL/6 mice and in neutropenic mutant Genista mouse model. We demonstrate that at later times of infection, Brucella abortus is killed more efficiently in the absence of PMNs than in their presence. The higher bacterial removal was concomitant to the: i comparatively reduced spleen swelling; ii augmented infiltration of epithelioid histiocytes corresponding to macrophages/dendritic cells (DCs; iii higher recruitment of monocytes and monocyte/DCs phenotype; iv significant activation of B and T lymphocytes, and v increased levels of INF-γ and negligible levels of IL4 indicating a balance of Th1 over Th2 response. These results reveal that PMNs have an unexpected influence in dampening the immune response against intracellular Brucella infection and strengthen the notion that PMNs actively participate in regulatory circuits shaping both innate and adaptive immunity.

  18. Human Monocyte-Derived Dendritic Cells Exposed to Microorganisms Involved in Hypersensitivity Pneumonitis Induce a Th1-Polarized Immune Response

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    Pallandre, Jean-René; Borg, Christophe; Loeffert, Sophie; Gbaguidi-Haore, Houssein; Millon, Laurence

    2013-01-01

    Hypersensitivity pneumonitis (HP) is an immunoallergic disease characterized by a prominent interstitial infiltrate composed predominantly of lymphocytes secreting inflammatory cytokines. Dendritic cells (DCs) are known to play a pivotal role in the lymphocytic response. However, their cross talk with microorganisms that cause HP has yet to be elucidated. This study aimed to investigate the initial interactions between human monocyte-derived DCs (MoDCs) and four microorganisms that are different in nature (Saccharopolyspora rectivirgula [actinomycetes], Mycobacterium immunogenum [mycobacteria], and Wallemia sebi and Eurotium amstelodami [filamentous fungi]) and are involved in HP. Our objectives were to determine the cross talk between MoDCs and HP-causative agents and to determine whether the resulting immune response varied according to the microbial extract tested. The phenotypic activation of MoDCs was measured by the increased expression of costimulatory molecules and levels of cytokines in supernatants. The functional activation of MoDCs was measured by the ability of MoDCs to induce lymphocytic proliferation and differentiation in a mixed lymphocytic reaction (MLR). E. amstelodami-exposed (EA) MoDCs expressed higher percentages of costimulatory molecules than did W. sebi-exposed (WS), S. rectivirgula-exposed (SR), or M. immunogenum-exposed (MI) MoDCs (P < 0.05, Wilcoxon signed-rank test). EA-MoDCs, WS-MoDCs, SR-MoDCs, and MI-MoDCs induced CD4+ T cell proliferation and a Th1-polarized immune response. The present study provides evidence that, although differences were initially observed between MoDCs exposed to filamentous fungi and MoDCs exposed to bacteria, a Th1 response was ultimately promoted by DCs regardless of the microbial extract tested. PMID:23720369

  19. Non-Esterified Fatty Acids Profiling in Rheumatoid Arthritis: Associations with Clinical Features and Th1 Response.

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    Javier Rodríguez-Carrio

    Full Text Available Since lipid compounds are known to modulate the function of CD4+ T-cells and macrophages, we hypothesize that altered levels of serum non-esterified fatty acids (NEFA may underlie rheumatoid arthritis (RA pathogenesis.Serum levels of NEFA (palmitic, stearic, palmitoleic, oleic, linoleic, γ-linoleic, arachidonic -AA-, linolenic, eicosapentaenoic -EPA- and docosahexaenoic -DHA- were quantified by LC-MS/MS after methyl-tert-butylether (MTBE-extraction in 124 RA patients and 56 healthy controls (HC. CD4+ phenotype was studied by flow cytometry. TNFα, IL-8, VEGF, GM-CSF, IFNγ, IL-17, CCL2, CXCL10, leptin and resistin serum levels were quantified by immunoassays. The effect of FA on IFNγ production by PBMC was evaluated in vitro.Lower levels of palmitic (p<0.0001, palmitoleic (p = 0.002, oleic (p = 0.010, arachidonic (p = 0.027, EPA (p<0.0001 and DHA (p<0.0001 were found in RA patients, some NEFA being altered at onset. Cluster analysis identified a NEFA profile (hallmarked by increased stearic and decreased EPA and DHA overrepresented in RA patients compared to HC (p = 0.002, being associated with clinical features (RF, shared epitope and erosions, increased IFNγ expression in CD4+ T-cells (p = 0.002 and a Th1-enriched serum milieu (IFNγ, CCL2 and CXCL10, all p<0.005. In vitro assays demonstrated that imbalanced FA could underlie IFNγ production by CD4+ T-cells. Finally, changes on NEFA levels were associated with clinical response upon TNFα-blockade.An altered NEFA profile can be found in RA patients associated with clinical characteristics of aggressive disease and enhanced Th1 response. These results support the relevance of lipidomic studies in RA and provide a rationale for new therapeutic targets.

  20. Oriental Medicine Samhwangsasim-tang Alleviates Experimental Autoimmune Encephalomyelitis by Suppressing Th1 Cell Responses and Upregulating Treg Cell Responses.

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    Lee, Min J; Choi, Jong H; Lee, Sung J; Cho, Ik-Hyun

    2017-01-01

    Oriental medicine Samhwangsasim-tang (SHSST) has traditionally been used in East Asia to treat hypertension and its complications. However, little is known about its potential value regarding the treatment of chronic inflammatory diseases such as multiple sclerosis (MS). In this study, we investigated whether SHSST has a beneficial effect in treating myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE). Onset-treatment with SHSST was found to alleviate neurological symptoms as well as demyelination and glial activation in the spinal cords from the EAE mice. The SHSST also attenuated the mRNA or protein expression of pro-inflammatory cytokines (interleukin-1beta and tumor necrotic factor-alpha); chemokines (RANTES, monocyte chemotactic protein-1, and macrophage inflammatory protein-1alpha); inducible nitric oxide synthase; and cyclooxygenase-2 in correspondence with the down-regulation of the nuclear factor-kappa B and mitogen-activated protein kinases signal pathways in the spinal cords from EAE mice. Interestingly, the protective effect of the SHSST was related to a decreased number of Th1 cells and an increased number of Treg cells in spinal cords from EAE mice. Taken together, our finding firstly suggested that SHSST could delay or mitigate EAE with a wide therapeutic time-window by suppressing Th1 cell responses and upregulating Treg cell responses. Also, our findings are strong enough to warrant further investigation of SHSST as a treatment for chronic autoimmune diseases including MS.

  1. Recombinant murine IL-12 promotes a protective Th1/cellular response in Mongolian gerbils infected with Sporothrix schenckii.

    Science.gov (United States)

    Flores-García, Aurelio; Velarde-Félix, Jesús Salvador; Garibaldi-Becerra, Vicente; Rangel-Villalobos, Héctor; Torres-Bugarín, Olivia; Zepeda-Carrillo, Eloy Alfonso; Ruíz-Bernés, Salvador; Ochoa-Ramírez, Luis Antonio

    2015-02-01

    Sporotrichosis is a cutaneous fungal infection caused by Sporothrix schenckii. It is known to be mainly contained by Th1 responses. As IL-12 is crucial for Th1 response, we investigated if treatment with recombinant murine IL-12 (rmIL-12) promoted Th1 immunity and/or clinical improvement in an experimental sporotrichosis gerbil model. Gerbils were inoculated with S. schenckii in the footpad and treated with rmIL-12. Seven days post infection there was a significant increase in macrophage phagocytosis and oxidative burst, and in delayed-type hypersensitivity (DTH) reaction in rmIL-12 treated gerbils, as well as a ∼10-fold increase of serum IFN-gamma and a decrease of IL-4 and IL-10. Moreover, rmIL-12 substantially decreased (∼70%) S. schenckii burden in liver and spleen and improved the clinical outcome preventing footpad ulcer and tail nodules observed in untreated gerbils. Our study demonstrates that rmIL-12 promotes Th1 immune response against S. schenckii favouring its clearance and preventing clinical symptoms.

  2. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section.

    Science.gov (United States)

    Jakobsson, Hedvig E; Abrahamsson, Thomas R; Jenmalm, Maria C; Harris, Keith; Quince, Christopher; Jernberg, Cecilia; Björkstén, Bengt; Engstrand, Lars; Andersson, Anders F

    2014-04-01

    The early intestinal microbiota exerts important stimuli for immune development, and a reduced microbial exposure as well as caesarean section (CS) has been associated with the development of allergic disease. Here we address how microbiota development in infants is affected by mode of delivery, and relate differences in colonisation patterns to the maturation of a balanced Th1/Th2 immune response. The postnatal intestinal colonisation pattern was investigated in 24 infants, born vaginally (15) or by CS (nine). The intestinal microbiota were characterised using pyrosequencing of 16S rRNA genes at 1 week and 1, 3, 6, 12 and 24 months after birth. Venous blood levels of Th1- and Th2-associated chemokines were measured at 6, 12 and 24 months. Infants born through CS had lower total microbiota diversity during the first 2 years of life. CS delivered infants also had a lower abundance and diversity of the Bacteroidetes phylum and were less often colonised with the Bacteroidetes phylum. Infants born through CS had significantly lower levels of the Th1-associated chemokines CXCL10 and CXCL11 in blood. CS was associated with a lower total microbial diversity, delayed colonisation of the Bacteroidetes phylum and reduced Th1 responses during the first 2 years of life.

  3. Cathepsin B in antigen-presenting cells controls mediators of the Th1 immune response during Leishmania major infection.

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    Iris J Gonzalez-Leal

    2014-09-01

    Full Text Available Resistance and susceptibility to Leishmania major infection in the murine model is determined by the capacity of the host to mount either a protective Th1 response or a Th2 response associated with disease progression. Previous reports involving the use of cysteine cathepsin inhibitors indicated that cathepsins B (Ctsb and L (Ctsl play important roles in Th1/Th2 polarization during L. major infection in both susceptible and resistant mouse strains. Although it was hypothesized that these effects are a consequence of differential patterns of antigen processing, the mechanisms underlying these differences were not further investigated. Given the pivotal roles that dendritic cells and macrophages play during Leishmania infection, we generated bone-marrow derived dendritic cells (BMDC and macrophages (BMM from Ctsb-/- and Ctsl-/- mice, and studied the effects of Ctsb and Ctsl deficiency on the survival of L. major in infected cells. Furthermore, the signals used by dendritic cells to instruct Th cell polarization were addressed: the expression of MHC class II and co-stimulatory molecules, and cytokine production. We found that Ctsb-/- BMDC express higher levels of MHC class II molecules than wild-type (WT and Ctsl-/- BMDC, while there were no significant differences in the expression of co-stimulatory molecules between cathepsin-deficient and WT cells. Moreover, both BMDC and BMM from Ctsb-/- mice significantly up-regulated the levels of interleukin 12 (IL-12 expression, a key Th1-inducing cytokine. These findings indicate that Ctsb-/- BMDC display more pro-Th1 properties than their WT and Ctsl-/- counterparts, and therefore suggest that Ctsb down-regulates the Th1 response to L. major. Moreover, they propose a novel role for Ctsb as a regulator of cytokine expression.

  4. Bordetella pertussis infection induces a mucosal IL-17 response and long-lived Th17 and Th1 immune memory cells in nonhuman primates.

    Science.gov (United States)

    Warfel, J M; Merkel, T J

    2013-07-01

    Despite near universal vaccine coverage, the bacterial pathogen Bordetella pertussis has re-emerged as a major public health concern. We recently developed a baboon (Papio anubis) model of pertussis that provides an excellent model of human pertussis. Using this model, the immune response to pertussis was characterized by measuring cytokines in the nasopharyngeal mucosa of infected baboons. Notably, we observed mucosal expression of interleukin-17 (IL-17) as well as IL-6, IL-23, and several cytokines and chemokines that are orchestrated by IL-17 immune responses. We also found substantial populations of circulating B. pertussis-specific Th17 and Th1 cells in convalescent animals >2 years post-infection consistent with a role in immunological memory to pertussis. Collectively, these data shed important light on the innate and adaptive immune responses to pertussis in a primate infection model and suggest that Th17 and Th1 immune responses contribute to the immunity conferred by natural pertussis infection.

  5. Long-Lasting Effects of BCG Vaccination on Both Heterologous Th1/Th17 Responses and Innate Trained Immunity

    DEFF Research Database (Denmark)

    Kleinnijenhuis, Johanneke; Quintin, Jessica; Preijers, Frank

    2013-01-01

    We have recently shown that BCG (Bacillus Calmette-Guérin) vaccination in healthy volunteers induces epigenetic reprogramming of monocytes, leading to increased cytokine production in response to nonrelated pathogens for up to 3 months after vaccination. This phenomenon was named 'trained immunity......'. In the present study we assessed whether BCG was able to induce long-lasting effects on both trained immunity and heterologous T helper 1 (Th1) and Th17 immune responses 1 year after vaccination. The production of TNFα and IL-1β to mycobacteria or unrelated pathogens was higher after 2 weeks and 3 months...... in proinflammatory cytokine production after stimulation with the TLR4 ligand lipopolysaccharide. The heterologous production of Th1 (IFN-γ) and Th17 (IL-17 and IL-22) immune responses to nonmycobacterial stimulation remained strongly elevated even 1 year after BCG vaccination. In conclusion, BCG induces sustained...

  6. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity.

    Science.gov (United States)

    Kleinnijenhuis, Johanneke; Quintin, Jessica; Preijers, Frank; Benn, Christine Stabell; Joosten, Leo A B; Jacobs, Cor; van Loenhout, Joke; Xavier, Ramnik J; Aaby, Peter; van der Meer, Jos W M; van Crevel, Reinout; Netea, Mihai G

    2014-01-01

    We have recently shown that BCG (Bacillus Calmette-Guérin) vaccination in healthy volunteers induces epigenetic reprogramming of monocytes, leading to increased cytokine production in response to nonrelated pathogens for up to 3 months after vaccination. This phenomenon was named 'trained immunity'. In the present study we assessed whether BCG was able to induce long-lasting effects on both trained immunity and heterologous T helper 1 (Th1) and Th17 immune responses 1 year after vaccination. The production of TNFα and IL-1β to mycobacteria or unrelated pathogens was higher after 2 weeks and 3 months postvaccination, but these effects were less pronounced 1 year after vaccination. However, monocytes recovered 1 year after vaccination had an increased expression of pattern recognition receptors such as CD14, Toll-like receptor 4 (TLR4) and mannose receptor, and this correlated with an increase in proinflammatory cytokine production after stimulation with the TLR4 ligand lipopolysaccharide. The heterologous production of Th1 (IFN-γ) and Th17 (IL-17 and IL-22) immune responses to nonmycobacterial stimulation remained strongly elevated even 1 year after BCG vaccination. In conclusion, BCG induces sustained changes in the immune system associated with a nonspecific response to infections both at the level of innate trained immunity and at the level of heterologous Th1/Th17 responses. Copyright © 2013 S. Karger AG, Basel

  7. Host Th1/Th2 immune response to Taenia solium cyst antigens in relation to cyst burden of neurocysticercosis.

    Science.gov (United States)

    Tharmalingam, J; Prabhakar, A T; Gangadaran, P; Dorny, P; Vercruysse, J; Geldhof, P; Rajshekhar, V; Alexander, M; Oommen, A

    2016-10-01

    Neurocysticercosis (NCC), Taenia solium larval infection of the brain, is an important cause of acquired seizures in endemic countries, which relate to number, location and degenerating cysts in the brain. Multicyst infections are common in endemic countries although single-cyst infection prevails in India. Single-cyst infections in an endemic country suggest a role for host immunity limiting the infection. This study examined ex vivo CD4(+) T cells and in vitro Th1 and Th2 cytokine responses to T. solium cyst antigens of peripheral blood mononuclear cells of healthy subjects from endemic and nonendemic regions and of single- and multicyst-infected patients for association with cyst burden of NCC. T. solium cyst antigens elicited a Th1 cytokine response in healthy subjects of T. solium-endemic and T. solium-non-endemic regions and those with single-cyst infections and a Th2 cytokine response from subjects with multicyst neurocysticercosis. Multicyst neurocysticercosis subjects also exhibited low levels of effector memory CD4(+) T cells. Th1 cytokine response of T. solium exposure and low infectious loads may aid in limiting cyst number. Th2 cytokines and low effector T cells may enable multiple-cyst infections to establish and persist. © 2016 John Wiley & Sons Ltd.

  8. Coincident diabetes mellitus modulates Th1-, Th2-, and Th17-cell responses in latent tuberculosis in an IL-10- and TGF-β-dependent manner.

    Science.gov (United States)

    Kumar, Nathella Pavan; Moideen, Kadar; George, Parakkal Jovvian; Dolla, Chandrakumar; Kumaran, Paul; Babu, Subash

    2016-02-01

    Type 2 diabetes mellitus (DM) is a risk factor for the development of active tuberculosis (TB), although its role in the TB-induced responses in latent TB (LTB) is not well understood. Since Th1, Th2, and Th17 responses are important in immunity to LTB, we postulated that coincident DM could alter the function of these CD4(+) T-cell subsets. To this end, we examined mycobacteria-induced immune responses in the whole blood of individuals with LTB-DM and compared them with responses of individuals without DM (LTB-NDM). T-cell responses from LTB-DM are characterized by diminished frequencies of mono- and dual-functional CD4(+) Th1, Th2, and Th17 cells at baseline and following stimulation with mycobacterial antigens-purified protein derivative, early secreted antigen-6, and culture filtrate protein-10. This modulation was at least partially dependent on IL-10 and TGF-β, since neutralization of either cytokine resulted in significantly increased frequencies of Th1 and Th2 cells but not Th17 cells in LTB-DM but not LTB individuals. LTB-DM is therefore characterized by diminished frequencies of Th1, Th2, and Th17 cells, indicating that DM alters the immune response in latent TB leading to a suboptimal induction of protective CD4(+) T-cell responses, thereby providing a potential mechanism for increased susceptibility to active disease. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Toxoplasma Co-infection Prevents Th2 Differentiation and Leads to a Helminth-Specific Th1 Response

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    Norus Ahmed

    2017-07-01

    Full Text Available Nematode infections, in particular gastrointestinal nematodes, are widespread and co-infections with other parasites and pathogens are frequently encountered in humans and animals. To decipher the immunological effects of a widespread protozoan infection on the anti-helminth immune response we studied a co-infection with the enteric nematode Heligmosomoides polygyrus in mice previously infected with Toxoplasma gondii. Protective immune responses against nematodes are dependent on parasite-specific Th2 responses associated with IL-4, IL-5, IL-13, IgE, and IgG1 antibodies. In contrast, Toxoplasma gondii infection elicits a strong and protective Th1 immune response characterized by IFN-γ, IL-12, and IgG2a antibodies. Co-infected animals displayed significantly higher worm fecundity although worm burden remained unchanged. In line with this, the Th2 response to H. polygyrus in co-infected animals showed a profound reduction of IL-4, IL-5, IL-13, and GATA-3 expressing T cells. Co-infection also resulted in the lack of eosinophilia and reduced expression of the Th2 effector molecule RELM-β in intestinal tissue. In contrast, the Th1 response to the protozoan parasite was not diminished and parasitemia of T. gondii was unaffected by concurrent helminth infection. Importantly, H. polygyrus specific restimulation of splenocytes revealed H. polygyrus-reactive CD4+ T cells that produce a significant amount of IFN-γ in co-infected animals. This was not observed in animals infected with the nematode alone. Increased levels of H. polygyrus-specific IgG2a antibodies in co-infected mice mirrored this finding. This study suggests that polarization rather than priming of naive CD4+ T cells is disturbed in mice previously infected with T. gondii. In conclusion, a previous T. gondii infection limits a helminth-specific Th2 immune response while promoting a shift toward a Th1-type immune response.

  10. Comparison of innate and Th1-type host immune responses inOesophagostomum dentatumandTrichuris suisinfections in pigs

    DEFF Research Database (Denmark)

    Andreasen, Annette; Skovgaard, Kerstin; Klaver, Elsenoor J.

    2016-01-01

    The present study investigated details of the innate and Th1/Treg type associated host immune responses in Trichuris suis and Oesophagostomum dentatum mono- and co-infected pigs and in vitro in stimulated porcine dendritic cell cultures. Forty-eight pigs were allocated into a 2-factorial design...... with two groups trickle inoculated with 10 T. suis eggs/kg/day (Group T) or 20 O. dentatum L3/kg/day (O). Another group (OT) was infected with both parasites. Group C remained uninfected. Expression of innate and Th1/Treg cell associated genes in gut mucosa and associated lymph nodes was determined by q......PCR at necropsy day 35 and 71. Gene expression showed suppressed/inhibited Th1 and Treg type immune reactions, in accordance with previous findings of a predominant Th2 type immune response to both nematodes. The in vitro part examined production of TNF-α in porcine dendritic cells (DC) exposed to T. suis and...

  11. PLGA nano/micro particles encapsulated with pertussis toxoid (PTd) enhances Th1/Th17 immune response in a murine model.

    Science.gov (United States)

    Li, Pan; Asokanathan, Catpagavalli; Liu, Fang; Khaing, Kyi Kyi; Kmiec, Dorota; Wei, Xiaoqing; Song, Bing; Xing, Dorothy; Kong, Deling

    2016-11-20

    Poly(lactic-co-glycolic acid) (PLGA) based nano/micro particles were investigated as a potential vaccine platform for pertussis antigen. Presentation of pertussis toxoid as nano/micro particles (NP/MP) gave similar antigen-specific IgG responses in mice compared to soluble antigen. Notably, in cell line based assays, it was found that PLGA based nano/micro particles enhanced the phagocytosis of fluorescent antigen-nano/micro particles by J774.2 murine monocyte/macrophage cells compared to soluble antigen. More importantly, when mice were immunised with the antigen-nano/micro particles they significantly increased antigen-specific Th1 cytokines INF-γ and IL-17 secretion in splenocytes after in vitro re-stimulation with heat killed Bordetalla pertussis, indicating the induction of a Th1/Th17 response. Also, presentation of pertussis antigen in a NP/MP formulation is able to provide protection against respiratory infection in a murine model. Thus, the NP/MP formulation may provide an alternative to conventional acellular vaccines to achieve a more balanced Th1/Th2 immune response. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Clinical influence of different intracanal medications on Th1-type and Th2-type cytokine responses in apical periodontitis.

    Science.gov (United States)

    Martinho, Frederico C; Nascimento, Gustavo G; Leite, Fabio R M; Gomes, Ana P M; Freitas, Lilian F; Camões, Izabel C G

    2015-02-01

    This clinical study assessed the influence of different intracanal medications on Th1-type and Th2-type cytokine responses in apical periodontitis and monitored the levels of bacteria from primarily infection during endodontic procedures. Thirty primarily infected teeth were randomly divided into 3 groups according to the medication selected: chlorhexidine (CHX), 2% CHX gel; Ca(OH)2/SSL, Ca(OH)2 + SSL; and Ca(OH)2/CHX, Ca(OH)2 + 2% CHX gel (all, n = 10). Bacterial sample was collected from root canals, and the interstitial fluid was sampled from lesions. Culture techniques were used to determine bacterial counts (colony-forming units/mL). Th1 (tumor necrosis factor-α, interferon-γ, and interleukin [IL]-2) and Th2 cytokines (IL-4, IL-5, and IL-13) were measured by enzyme-linked immunosorbent assay. All intracanal medication protocols were effective in reducing the bacterial load from root canals (all P type cytokines in apical lesions (all P .05). Both Ca(OH)2 treatment protocols significantly increased the levels of Th2-type cytokines (P .05). Thus, chlorhexidine medication showed the lowest effectiveness in increasing the levels of Th2-type cytokine. After treatment, regardless of the type of medication, the linear regression analysis indicated the down-regulation of Th2-type cytokines by Th1-type cytokines. All intracanal medication protocols were effective in reducing bacterial load and lowering the levels of Th1-type cytokines. Thus, the use of Ca(OH)2 medications contributed to the increase in the Th2-type cytokine response in apical periodontitis. Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  13. Th1 and Th2 immune response to P30 and ROP18 peptides in human toxoplasmosis.

    Science.gov (United States)

    Torres-Morales, Elizabeth; Taborda, Laura; Cardona, Nestor; De-la-Torre, Alejandra; Sepulveda-Arias, Juan Carlos; Patarroyo, Manuel Alfonso; Gomez-Marin, Jorge Enrique

    2014-10-01

    We determined the specific lymphocyte proliferative response and cytokine profile production regarding Toxoplasma P30 (2017 from virulent and non-virulent strain) and ROP18 protein-derived peptides (from clonal lineages I, II and III) in 19 patients having ocular toxoplasmosis, five suffering chronic asymptomatic infection, nine with congenital toxoplasmosis and eight Toxoplasma negative people. A Beckman Coulter FC500 flow cytometer was used for determining antigen-specific T cells (CD3+ CD4+ or CD3+ CD8+ cells) in peripheral blood culture. IFN γ and IL10 levels were determined in culture supernatants. Specific CD4+ and CD8+ T cell response to total antigen and P30- and ROP18-derived peptides was observed in infected people. Ocular toxoplasmosis patients had a preferential Th2 response after antigenic stimulation. Non-virulent peptide 2017 was able to shift response toward Th1 in congenitally infected children and virulent peptide 2017 induced a Th2 response in chronically infected, asymptomatic people. An immune response in human toxoplasmosis after ex vivo antigenic stimulation was Th1- or Th2-skewed, depending on a patient's clinical condition. Colombian ocular toxoplasmosis patients' immune response was Th2-skewed, regardless of the nature of antigen stimulus.

  14. Indications of Th1 and Th17 responses in cerebrospinal fluid from patients with Lyme neuroborreliosis: a large retrospective study

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    Malmvall Bo-Eric

    2011-04-01

    Full Text Available Abstract Background Previous studies indicate that successful resolution of Lyme neuroborreliosis (NB is associated with a strong T helper (Th 1-type cytokine response in the cerebrospinal fluid (CSF followed by a down-regulating Th2 response, whereas the role of the recently discovered Th17 cytokine response is unknown. Methods To investigate the relative contribution of different Th associated cytokine/chemokine responses, we used a multiple bead array to measure the levels of CXCL10 (Th1 marker, CCL22 (Th2 marker, IL-17 (Th17 marker and CXCL8 (general inflammation marker, in serum and in CSF from untreated patients with confirmed NB (n = 133, and non-NB patients (n = 96, and related the findings to clinical data. Samples from patients with possible early NB (n = 15 and possible late NB (n = 19 were also analysed, as well as samples from an additional control group with orthopaedic patients (n = 17, where CSF was obtained at spinal anaesthesia. Results The most prominent differences across groups were found in the CSF. IL-17 was elevated in CSF in 49% of the patients with confirmed NB, but was not detectable in the other groups. Patients with confirmed NB and possible early NB had significantly higher CSF levels of CXCL10, CCL22 and CXCL8 compared to both the non-NB group and the control group (p Borrelia-antibodies. Conclusion Our results support the notion that early NB is dominated by a Th1-type response, eventually accompanied by a Th2 response. Interestingly, IL-17 was increased exclusively in CSF from patients with confirmed NB, suggesting a hitherto unknown role for Th17 in NB. However, for conclusive evidence, future prospective studies are needed.

  15. Berberine Attenuates Inflammation Associated with Delayed-Type Hypersensitivity via Suppressing Th1 Response and Inhibiting Apoptosis.

    Science.gov (United States)

    Wang, Zhigang; Chen, Zhe; Chen, Tao; Yi, Tao; Zheng, Zhou; Fan, Hong; Chen, Zebin

    2017-02-01

    Berberine, one of the active alkaloids from Rhizoma Coptidis, has been indicated to have anti-inflammatory and immunosuppressive properties. The aim of this study was to determine the role of berberine on ovalbumin (OVA)-induced delayed-type hypersensitivity (DTH) and its potential mechanisms. Berberine treatment significantly reduced footpad swelling, inflammatory cells infiltration, anti-OVA IgG levels, IgE concentration in serum, and the tetramer(+)CD8(+) cells. In homogenized footpad tissue, the production of Th1-mediated cytokines including IFN-γ, TNF-α, and IL-2 were suppressed following the administration of berberine. Detailed studies revealed that berberine prevented differentiation into Th1 cells in the OVA-primed lymphocytes, resulting from suppressing the expression of T-bet and secretion of IFN-γ but not IL-4. Concanavalin A stimulation assay and MTT assay also indicated inhibiting effect of berberine treatment on IFN-γ production and decreased cytotoxicity in lymphocytes proliferation, respectively. Additionally, berberine obviously decreased the cell apoptosis and enzymatic activity of caspase-3, which was further confirmed by the facts that berberine clearly lowered Bax/Bcl-2 ratio and expression of cleaved caspase-3 protein. On correlation analysis, the percentage of apoptotic cells showed a significant positive relationship with IFN-γ/IL-4 ratio of supernatant from footpad tissue in berberine-treated DTH mice. These results demonstrated that berberine attenuated Th1-mediated inflammation in OVA-induced DTH by curbing Th1 response and inhibiting cell apoptosis, suggesting a therapeutic potential for berberine for the treatment of type IV hypersensitivity.

  16. Induction of antigen-specific Th1-type immune responses by gamma-irradiated recombinant Brucella abortus RB51.

    Science.gov (United States)

    Sanakkayala, Neelima; Sokolovska, Anna; Gulani, Jatinder; Hogenesch, Harm; Sriranganathan, Nammalwar; Boyle, Stephen M; Schurig, Gerhardt G; Vemulapalli, Ramesh

    2005-12-01

    Brucella abortus strain RB51 is an attenuated rough mutant used as the live vaccine against bovine brucellosis in the United States and other countries. We previously reported the development of strain RB51 as a bacterial vaccine vector for inducing Th1-type immune responses against heterologous proteins. Because safety concerns may preclude the use of strain RB51-based recombinant live vaccines, we explored the ability of a gamma-irradiated recombinant RB51 strain to induce heterologous antigen-specific immune responses in BALB/c mice. Exposure of strain RB51G/LacZ expressing Escherichia coli beta-galactosidase to a minimum of 300 kilorads of gamma radiation resulted in complete loss of replicative ability. These bacteria, however, remained metabolically active and continued to synthesize beta-galactosidase. A single intraperitoneal inoculation of mice with 10(9) CFU equivalents of gamma-irradiated, but not heat-killed, RB51G/LacZ induced a beta-galactosidase-specific Th1-type immune response. Though no obvious differences were detected in immune responses to B. abortus-specific antigens, mice vaccinated with gamma-irradiated, but not heat-killed, RB51G/LacZ developed significant protection against challenge with virulent B. abortus. In vitro experiments indicated that gamma-irradiated and heat-killed RB51G/LacZ induced maturation of dendritic cells; however, stimulation with gamma-irradiated bacteria resulted in more interleukin-12 secretion. These results suggest that recombinant RB51 strains exposed to an appropriate minimum dose of gamma radiation are unable to replicate but retain their ability to stimulate Th1 immune responses against the heterologous antigens and confer protection against B. abortus challenge in mice.

  17. Notch-ligand expression by NALT dendritic cells regulates mucosal Th1- and Th2-type responses

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    Fukuyama, Yoshiko; Tokuhara, Daisuke [Department of Pediatric Dentistry, The Immunobiology Vaccine Center, The Institute of Oral Health Research, The University of Alabama at Birmingham, Birmingham, AL 35294-0007 (United States); Division of Mucosal Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639 (Japan); Sekine, Shinichi [Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Osaka 565-0871 (Japan); Kataoka, Kosuke [Department of Preventive Dentistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504 (Japan); Markham, Jonathan D.; Irwin, Allyson R.; Moon, Grace H.; Tokuhara, Yuka; Fujihashi, Keiko [Department of Pediatric Dentistry, The Immunobiology Vaccine Center, The Institute of Oral Health Research, The University of Alabama at Birmingham, Birmingham, AL 35294-0007 (United States); Davydova, Julia; Yamamoto, Masato [Department of Surgery, University of Minnesota, Minneapolis, MN 55455 (United States); Gilbert, Rebekah S. [Department of Pediatric Dentistry, The Immunobiology Vaccine Center, The Institute of Oral Health Research, The University of Alabama at Birmingham, Birmingham, AL 35294-0007 (United States); Fujihashi, Kohtaro, E-mail: kohtarof@uab.edu [Department of Pediatric Dentistry, The Immunobiology Vaccine Center, The Institute of Oral Health Research, The University of Alabama at Birmingham, Birmingham, AL 35294-0007 (United States)

    2012-02-03

    Highlights: Black-Right-Pointing-Pointer Nasal Ad-FL effectively up-regulates APC function by CD11c{sup +} DCs in mucosal tissues. Black-Right-Pointing-Pointer Nasal Ad-FL induces Notch ligand (L)-expressing CD11c{sup +} DCs. Black-Right-Pointing-Pointer Notch L-expressing DCs support the induction of Th1- and Th2-type cytokine responses. -- Abstract: Our previous studies showed that an adenovirus (Ad) serotype 5 vector expressing Flt3 ligand (Ad-FL) as nasal adjuvant activates CD11c{sup +} dendritic cells (DCs) for the enhancement of antigen (Ag)-specific IgA antibody (Ab) responses. In this study, we examined the molecular mechanism for activation of CD11c{sup +} DCs and their roles in induction of Ag-specific Th1- and Th2-cell responses. Ad-FL activated CD11c{sup +} DCs expressed increased levels of the Notch ligand (L)-expression and specific mRNA. When CD11c{sup +} DCs from various mucosal and systemic lymphoid tissues of mice given nasal OVA plus Ad-FL were cultured with CD4{sup +} T cells isolated from non-immunized OVA TCR-transgenic (OT II) mice, significantly increased levels of T cell proliferative responses were noted. Furthermore, Ad-FL activated DCs induced IFN-{gamma}, IL-2 and IL-4 producing CD4{sup +} T cells. Of importance, these APC functions by Ad-FL activated DCs were down-regulated by blocking Notch-Notch-L pathway. These results show that Ad-FL induces CD11c{sup +} DCs to the express Notch-ligands and these activated DCs regulate the induction of Ag-specific Th1- and Th2-type cytokine responses.

  18. Mycobacterium vaccae induces a strong Th1 response that subsequently declines in C57BL/6 mice.

    Science.gov (United States)

    Zhang, Lijiao; Jiang, Yanlong; Cui, Ziyin; Yang, Wentao; Yue, Limin; Ma, Yingcong; Shi, Shaohua; Wang, Chunfang; Wang, Chunfeng; Qian, Aidong

    2016-12-30

    Mycobacterium (M.) vaccae is a fast-growing species of saprophytic bacteria that is widely distributed. To understand the host immune responses induced by M. vaccae isolated from bovine submaxillary lymph nodes, C57BL/6 mice were infected with reference strain M. bovis Bacillus Calmette-Guérin (BCG) and isolated M. vaccae using intraperitoneal injections. Comparison of the bacterial replication and organ pathology between M. vaccae and M. bovis BCG revealed that M. vaccae was more malignant than M. bovis in mice. We also demonstrated that serum from the M. vaccae-infected mice contained a higher expression level of gamma-interferon (IFN-γ), tumor necrosis factor alpha, monocyte chemoattractant protein-1, interleukin (IL)-4, IL-12, IL-10 and transforming growth factor beta than did the other groups, especially after week 4. Furthermore, when the numbers of CD3⁺CD4⁺IFN-γ⁺ and CD3⁺CD4⁺IL4⁺cells in the infected mice were observed by flow cytometry, we found that a powerful T helper 1 (Th1) response was induced by M. vaccae infection, which was associated with the emergence of CD3⁺CD4⁺IFN-γ⁺cells. However, the Th1 response declined over time, which was associated with appearance of the CD4⁺CD25⁺FoxP3⁺ and CD4⁺CD25⁺CD152⁺Treg cell reaction. In addition, a strong Th2 response was found. Finally, we found that M. vaccae infection increased the production of type I IFNs, which was associated with a reduced Th1 response.

  19. The Mycobacterium bovis BCG prime-Rv0577 DNA boost vaccination induces a durable Th1 immune response in mice.

    Science.gov (United States)

    Gu, Dongqing; Chen, Wei; Mi, Youjun; Gong, Xueli; Luo, Tao; Bao, Lang

    2016-04-01

    Tuberculosis remains a major global health problem and effective vaccines are urgently needed. In this study, we used the combined DNA- and protein-based vaccines of immunodominant antigen Rv0577 to boost BCG and evaluated their immunogenicity in BALB/c mice. Our data suggest that the booster vaccine may substantially enhance the immunogenicity of BCG and strengthen both CD4+ T cell-mediated Th1 and CD8+ T cell-mediated cytolytic responses. Compared with the protein-based vaccine, the DNA-based vaccine can induce more durable Th1 immune response, characterized by high levels of antibody response, proliferation response, percentages of CD4+/CD8+ and cytokine secretion in antigen-stimulated splenocyte cultures. In conclusion, we for the first time, developed a protein- and plasmid DNA-based booster vaccine based on Rv0577. Our findings suggest that antigen Rv0577-based DNA vaccine is immunogenic and can efficiently boost BCG, which could be helpful in the design of an efficient vaccination strategy against TB. © The Author 2016. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

  20. Interferon-Alpha Promotes Th1 Response and Epithelial Apoptosis via Inflammasome Activation in Human Intestinal MucosaSummary

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    Anne Jarry

    2017-01-01

    Full Text Available Backgound & Aims: Several lines of investigation suggest that interferon (IFN alpha can alter human intestinal mucosa homeostasis. These include the endogenous production of IFN alpha in celiac disease or inflammatory bowel diseases, as well as the occurrence of intestinal side effects of exogenous IFN alpha used as a therapeutic tool. Here, we present an ex vivo translational approach to investigate the effects of IFN alpha on the human normal intestinal mucosa, as well as its underlying mechanisms. Methods: Human normal colonic mucosa explants were cultured in the presence or absence of IFN alpha 2a. Epithelial homeostasis was assessed using the immunohistochemical marker of apoptosis M30. The Wnt inhibitor Dickkopf-Homolog-1 (DKK1 was assayed in the supernatants by enzyme-linked immunosorbent assay. Activation of the inflammasome (caspase-1/interleukin [IL]18 and of a Th1 response was determined by in situ detection of active caspase-1, as well as by measurement of mature IL18 production and the prototype Th1 cytokine IFN gamma by enzyme-linked immunosorbent assay. In addition, mechanistic studies were performed using the specific caspase-1 inhibitor Tyr-Val-Ala-Asp(OMe-fluoromethylketone (YVAD-FMK, IL18-binding protein, neutralizing anti–IFN gamma, and anti-DKK1 antibodies. Results: IFN alpha 2a elicited a rapid (24 hours disruption of surface and crypt colonic epithelial cells via apoptosis that was variable in intensity among the 20 individuals studied. This apoptotic effect was dependent on the initiation of an IFN gamma response elicited by resident T box expressed in T cells–positive lamina propria cells. Both apoptosis and Th1 response were subordinated to active caspase-1 and IL18 production. Finally, neutralization of IFN gamma–induced DKK1 partially protected against IFN alpha–induced epithelial apoptosis. Conclusions: By using an ex vivo model, we show an interindividual heterogeneity of IFN alpha effects

  1. Levamisole promotes murine bone marrow derived dendritic cell activation and drives Th1 immune response in vitro and in vivo.

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    Fu, Yubing; Wang, Ting; Xiu, Lei; Shi, Xiaojie; Bian, Ziyao; Zhang, Yongli; Ruhan, A; Wang, Xiao

    2016-02-01

    Our lab previously found that levamisole (LMS) as an adjuvant enhanced the efficacy of vaccine against infectious pathogens. However, the cellular and molecular mechanisms remain to be defined. In this study, we showed that BALB/c bone marrow-derived DC stimulated with LMS resulted in enhanced cell-surface expression of CD80, CD86, CD40 and MHC class II, as well as enhanced production of IL-12p70, TNF-α and IL-1β. Interestingly, the LMS activated DCs were able to stimulate CD4(+) T cell proliferation and facilitated Th1 differentiation by increasing the secretion of IFN-γ in an allogeneic mixed leukocyte reaction. Furthermore, to confirm the in vitro data, we investigated the effect of LMS on antigen-specific antibody and cytokine production in BALB/c mice. Immunization with LMS plus OVA showed that anti-OVA IgG2a and IFN-γ were increased significantly compared with OVA alone in BALB/c mice. In conclusion, our results suggested that murine bone marrow-derived DC, played a crucial role in the effect of LMS on the induction of Th1 responses, which probably was due to its ability to promote DC maturation and secrete proinflammatory cytokines. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Vitamin E-rich Nanoemulsion Enhances the Antitumor Efficacy of Low-Dose Paclitaxel by Driving Th1 Immune Response.

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    Ye, Jun; Dong, Wujun; Yang, Yanfang; Hao, Huazhen; Liao, Hengfeng; Wang, Bangyuan; Han, Xue; Jin, Yiqun; Xia, Xuejun; Liu, Yuling

    2017-06-01

    To overcome the drawbacks of high dose regimen and improve the outcomes of chemotherapy at a low dose, an immunotherapeutic nanoemulsion based combination of chemotherapeutic agent (paclitaxel) with immunomodulatory agent (vitamin E) was developed and evaluated for their antitumor effect against breast cancer. A total of five nanoemulsions loaded with various content of vitamin E were prepared and characterized. The immunoregulatory effects of vitamin E along with the overall antitumor efficacy of vitamin E-rich nanoemulsion with a low dose of paclitaxel were investigated through in vitro and in vivo experiments. Vitamin E-rich nanoemulsion exhibited relatively narrow size distribution, high entrapment efficiency and controlled in vitro release profile. In RAW264.7 cells, vitamin E-rich nanoemulsion significantly enhanced the secretion of Th1 cytokines and down-regulated the secretion of Th2 cytokine. In a co-culture system, vitamin E-rich nanoemulsion induced a high apoptosis rate in MDA-MB-231 cells as compared with vitamin E-low nanoemulsion. Furthermore, vitamin E-rich nanoemulsion exhibited superior in vivo antitumor efficacy in comparison with Taxol and vitamin E-low nanoemulsion at a paclitaxel dose of 4 mg/kg. Vitamin E-rich nanoemulsion has great potential for the treatment of breast cancers with a low dose of paclitaxel via driving Th1 immune response.

  3. Enhancement of a TH1 Immune Response in Amphotericin B-Treated Mucocutaneous Leishmaniasis

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    Washington R. Cuna

    2007-01-01

    Full Text Available In an attempt to investigate the effects of treatment of human leishmaniasis, the cytokines produced by peripheral blood mononuclear cells (PBMCs of patients with cutaneous leishmaniasis (CL and mucocutaneous leishmaniasis (MCL under treatment with amphotericin B were determined during the active disease from cocultures of cells and Leishmania (Viannia braziliensis antigens. PBMC of these patients exhibited a nonsignificant marginal increased production of TNF-α upon antigen stimulation. However, under the same antigenic stimulus, patients with active MCL presented higher IFN-γ production compared to patients with CL. This increased IFN-γ production was accompanied by a drastically augmented IL-12 synthesis from cells of MCL patients. The highlighted T cell responses could be relevant for sound control measures of protozoan infections with emphasis on the combined usage of immunoenhancing agents and antiprotozoal drugs.

  4. Staphylococcus aureus-derived extracellular vesicles induce neutrophilic pulmonary inflammation via both Th1 and Th17 cell responses.

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    Kim, M-R; Hong, S-W; Choi, E-B; Lee, W-H; Kim, Y-S; Jeon, S G; Jang, M H; Gho, Y S; Kim, Y-K

    2012-10-01

    Recent evidence indicates that Staphylococcus aureus, one of the most important human pathogens, secretes vesicles into the extracellular milieu. To evaluate whether inhalation of S. aureus-derived extracellular vesicles (EV) is causally related to the pathogenesis of inflammatory pulmonary diseases. Staphylococcus aureus EV were prepared by sequential ultrafiltration and ultracentrifugation. The innate immune response was evaluated in vitro after the application of EV to airway epithelial cells and alveolar macrophages. In vivo innate and adaptive immune responses were evaluated after airway exposure to EV. Adjuvant effects of EV on the development of hypersensitivity to inhaled allergens were also evaluated after airway sensitization with S. aureus EV and ovalbumin (OVA). Staphylococcus aureus and S. aureus EV were detected in house dust. Alveolar macrophages produced both tumor necrosis α (TNF-α) and interleukin 6 (IL-6) after in vitro stimulation with S. aureus EV, whereas airway epithelial cells produced only IL-6. Repeated airway exposure to S. aureus EV induced both Th1 and Th17 cell responses and neutrophilic pulmonary inflammation, mainly via a Toll-like receptor 2 (TLR2)-dependent mechanism. In terms of adjuvant effects, airway sensitization with S. aureus EV and OVA resulted in neutrophilic pulmonary inflammation after OVA challenge alone. This phenotype was partly reversed by the absence of interferon γ (IFN-γ) or IL-17. Staphylococcus aureus EV can induce Th1 and Th17 neutrophilic pulmonary inflammation, mainly in a TLR2-dependent manner. Additionally, S. aureus EV enhance the development of airway hypersensitivity to inhaled allergens. © 2012 John Wiley & Sons A/S.

  5. Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation.

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    Marks, E; Naudin, C; Nolan, G; Goggins, B J; Burns, G; Mateer, S W; Latimore, J K; Minahan, K; Plank, M; Foster, P S; Callister, R; Veysey, M; Walker, M M; Talley, N J; Radford-Smith, G; Keely, S

    2017-09-01

    Intestinal inflammatory lesions are inherently hypoxic, due to increased metabolic demands created by cellular infiltration and proliferation, and reduced oxygen supply due to vascular damage. Hypoxia stabilizes the transcription factor hypoxia-inducible factor-1α (HIF) leading to a coordinated induction of endogenously protective pathways. We identified IL12B as a HIF-regulated gene and aimed to define how the HIF-IL-12p40 axis influenced intestinal inflammation. Intestinal lamina propria lymphocytes (LPL) were characterized in wild-type and IL-12p40 -/- murine colitis treated with vehicle or HIF-stabilizing prolyl-hydroxylase inhibitors (PHDi). IL12B promoter analysis was performed to examine hypoxia-responsive elements. Immunoblot analysis of murine and human LPL supernatants was performed to characterize the HIF/IL-12p40 signaling axis. We observed selective induction of IL-12p40 following PHDi-treatment, concurrent with suppression of Th1 and Th17 responses in murine colitis models. In the absence of IL-12p40, PHDi-treatment was ineffective. Analysis of the IL12B promoter identified canonical HIF-binding sites. HIF stabilization in LPLs resulted in production of IL-12p40 homodimer which was protective against colitis. The selective induction of IL-12p40 by HIF-1α leads to a suppression of mucosal Th1 and Th17 responses. This HIF-IL12p40 axis may represent an endogenously protective mechanism to limit the progression of chronic inflammation, shifting from pro-inflammatory IL-12p70 to an antagonistic IL-12p40 homodimer.

  6. Protective Live Oral Brucellosis Vaccines Stimulate Th1 and Th17 Cell Responses

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    Clapp, Beata; Skyberg, Jerod A.; Yang, Xinghong; Thornburg, Theresa; Walters, Nancy; Pascual, David W.

    2011-01-01

    Zoonotic transmission of brucellosis often results from exposure to Brucella-infected livestock, feral animals, or wildlife or frequently via consumption of unpasteurized milk products or raw meat. Since natural infection of humans often occurs by the oral route, mucosal vaccination may offer a means to confer protection for both mucosal and systemic tissues. Significant efforts have focused on developing a live brucellosis vaccine, and deletion of the znuA gene involved in zinc transport has been found to attenuate Brucella abortus. A similar mutation has been adapted for Brucella melitensis and tested to determine whether oral administration of ΔznuA B. melitensis can confer protection against nasal B. melitensis challenge. A single oral vaccination with ΔznuA B. melitensis rapidly cleared from mice within 2 weeks and effectively protected mice upon nasal challenge with wild-type B. melitensis 16M. In 83% of the vaccinated mice, no detectable brucellae were found in their spleens, unlike with phosphate-buffered saline (PBS)-dosed mice, and vaccination also enhanced the clearance of brucellae from the lungs. Moreover, vaccinated gamma interferon-deficient (IFN-γ−/−) mice also showed protection in both spleens and lungs, albeit protection that was not as effective as in immunocompetent mice. Although IFN-γ, interleukin 17 (IL-17), and IL-22 were stimulated by these live vaccines, only RB51-mediated protection was codependent upon IL-17 in BALB/c mice. These data suggest that oral immunization with the live, attenuated ΔznuA B. melitensis vaccine provides an attractive strategy to protect against inhalational infection with virulent B. melitensis. PMID:21768283

  7. DDA/TDB liposomes containing soluble Leishmania major antigens induced a mixed Th1/Th2 immune response in BALB/c mice

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    Mansure Hojatizade

    2017-04-01

    Full Text Available Objective(s: Leishmaniasis is a complex parasitic disease that represents a major public health problem. Despite numerous attempts over the past decades, yet there is no effective vaccine against human leishmaniasis probably due to the lack of suitable adjuvants. In this study, a first generation liposomal-based Leishmania vaccine was developed using soluble Leishmania major antigens (SLA and á, Ü-trehalose6, 6'-dibehenat (TDB as an immunostimulatory adjuvant. In this liposome structure, the cationic lipid Dimethyldioctadecylammonium (DDA provides intrinsic adjuvant activity and cholesterol was added as a membrane stabilizer. Liposomes containing SLA were prepared.Materials and Methods: BALB/c mice were subcutaneously (sc immunized with Lip (DDA/TDB/CHOL-SLA+, Lip (DDA/TDB-SLA+, Lip (DDA-SLA+, Lip (DDA/CHOL-SLA+, SLA or Tris-HCl buffer. Immunization was done every two weeks for three weeks. The immunized mice were then challenged sc in the left footpad with 1×106 stationary phase L. major promastigotes (50 ìl, at 2 weeks after last booster injection.Results: mice immunized with any of the liposomal formulations containing SLA (Lip-SLA+, substantially increased footpad swelling and parasite loads of foot and spleen with no significant difference compared to Tris-HCl buffer or SLA alone. Lip-SLA+ formulations induced a mixed Th1/Th2 immune response characterized by IFN-ã and IL-4 production as well as high levels of IgG1 anti-Leishmania antibody. Conclusion: immunization with liposomes containing DDA and/or TDB in combination with SLA induces a mixed Th1/Th2 immune response and is not an appropriate strategy for preferential induction of a Th1 response and protection against leishmaniasis.

  8. Immunization with Paracoccidioides brasiliensis radioattenuated yeast cells induces Th1 immune response in Balb/C mice

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    Martins, Estefania M.N.; Andrade, Antero S.R. [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN-CNEN/MG), Belo Horizonte, MG (Brazil)], e-mail: estefaniabio@yahoo.com.br, e-mail: antero@cdtn.br; Resende, Maria Aparecida de [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Dept. de Microbiologia], e-mail: maresend@mono.icb.ufmg.br; Reis, Bernardo S.; Goes, Alfredo M. [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Dept. de Bioquimica e Imunologia], e-mail: goes@mono.icb.ufmg.br, e-mail: brsgarbi@mono.icb.ufmg.br

    2009-07-01

    Paracoccidioides brasiliensis is the agent of paracoccidioidomycosis, the most prevalent mycosis in Latin America. To date, there is no effective vaccine. In our laboratory yeast cells of P. brasiliensis were attenuated by gamma irradiation. We defined an absorbed dose in which the pathogen loses the reproductive ability, while retaining the morphology, the synthesis and secretion of proteins and the oxidative metabolism. The immunization with these cells was able to confer protection in BALB/c mice. The aim of the present work was evaluate the immune response pathway activated in mice immunized with P. brasiliensis radioattenuated yeast cells. The protector effect was evaluated in BALB/c mice groups immunized once or twice, respectively. Each group was divided in three sub groups that were challenge 30, 45 or 60 days after the immunization. These groups were called G1A, G1B and G1C in the group immunized once and G2A, G2B and G2C in the group immunized twice. Recovery of CFUs and cytokines determination (IFN - {gamma}, IL - 10 and IL IV 4) were performed three months post challenge. Quantitative RT-PCR was the method of choice used to quantify the expression of cytokines. The sera were collected weekly to evaluate the IgG antibody titers and the IgG1 and IgG2a pattern in the course of infection. A significant reduction in CFUs recovery was verified 90 days post challenge in mice submitted to one immunization: 73.0%, 96.0% and 76.3% for sub-groups G1A, G1B and G1C, respectively. In the group submitted to two immunizations, a remarkable increase in the protection was obtained. No CFUs was recovered from sub-groups G2B and G2C and very few CFUs (reduction of 98.6%) were recovered from the lungs of sub group G2A. In mice submitted to one immunization, Th1 and Th2 cytokines were simultaneously produced. In the group submitted to two immunizations, levels of IL-10 and IL-4 were very low, while IFN-{gamma} production was maintained indicating that a Th1 pattern was

  9. A pcDNA-Ehcpadh vaccine against Entamoeba histolytica elicits a protective Th1-like response in hamster liver.

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    Martínez, Máximo B; Rodríguez, Mario A; García-Rivera, Guillermina; Sánchez, Tomás; Hernández-Pando, Rogelio; Aguilar, Diana; Orozco, Esther

    2009-06-24

    DNA vaccines are promising tools to fight parasitic diseases, including amoebiasis caused by the protozoan Entamoeba histolytica. Here we studied the immunogenicity and protective efficacy of a DNA vaccine against this parasite composed by the EhCPADH surface complex encoding genes (Ehcp112 and Ehadh112). EhCPADH is formed by an adhesin (EhADH112) and a cysteine proteinase (EhCP112), both involved in the parasite virulence. We evaluated transcription, protein expression, immunological response and protection against hepatic amoebiasis in hamsters intradermally and intramuscularly immunized with a mixture of pcDNA-Ehadh112 and pcDNA-Ehcp112 plasmids. RT-PCR and immunohistochemical assays showed that both antigens were differentially expressed in spleen and liver of immunized animals. No significant antibody immune response was induced by either route. However, intradermally inoculated hamsters presented a robust Th1-like immune response, characterized by high levels of INF-gamma and TNF-alpha cytokines, detected in the liver of animals challenged with virulent trophozoites. Animals showed significant protection against amoebiasis manifested by a higher survival rate and a significant prevention of liver abscess formation. We conclude that a refinement of this DNA vaccine could be a good choice to control hepatic amoebiasis.

  10. Heavy metal mediated innate immune responses of the Indian green frog, Euphlyctis hexadactylus (Anura: Ranidae): Cellular profiles and associated Th1 skewed cytokine response

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    Jayawardena, Uthpala A.; Ratnasooriya, Wanigasekara D.; Wickramasinghe, Deepthi D.; Udagama, Preethi V., E-mail: dappvr@yahoo.com

    2016-10-01

    Immune cell and cytokine profiles in relation to metal exposure though much studied in mammals has not been adequately investigated in amphibians, due mainly to lack of suitable reagents for cytokine profiling in non-model species. However, interspecies cross reactivity of cytokines permitted us to assay levels of IFNγ, TNFα, IL6 and IL10in a common anuran, the Indian green frog (Euphlyctis hexadactylus), exposed to heavy metals (Cd, Cr, Cu, Zn and Pb, at ~ 5 ppm each) under field and laboratory settings in Sri Lanka. Enumeration of immune cells in blood and melanomacrophages in the liver, assay of serum and hepatic cytokines, and Th1/Th2 cytokine polarisation were investigated. Immune cell counts indicated overall immunosuppression with decreasing total WBC and splenocyte counts while neutrophil/lymphocyte ratio increased with metal exposure, indicating metal mediated stress. Serum IL6 levels of metal exposed frogs reported the highest (~ 9360 pg/mL) of all cytokines tested. Significantly elevated IFNγ production (P < 0.05) was evident in heavy metal exposed frogs. Th1/Th2 cytokine ratio in both serum and liver tissue homogenates was Th1 skewed due to significantly higher production of pro-inflammatory cytokines, IFNγ in serum and TNFα in the liver (P < 0.01).Metal mediated aggregations of melanomacrophages in the liver were positively and significantly (P < 0.05) correlated with the hepatic expression of TNFα, IL6 and IL10 activity. Overall, Th1 skewed response may well be due to oxidative stress mediated nuclear factor κ-light chain enhancer of activated B cells (NFκB) which enhances the transcription of pro-inflammatory cytokines. Xenobiotic stress has recently imposed an unprecedented level of threat to wildlife, particularly to sensitive species such as amphibians. Therefore, understanding the interactions between physiological stress and related immune responses is fundamental to conserve these environmental sentinels in the face of emerging eco

  11. Immunopathology and Th1/Th2 immune response of Campylobacter jejuni-induced paralysis resembling Guillain-Barré syndrome in chicken.

    Science.gov (United States)

    Nyati, Kishan K; Prasad, Kashi N; Kharwar, Nagendra K; Soni, Priyanka; Husain, Nuzhat; Agrawal, Vinita; Jain, Arun K

    2012-05-01

    Immunopathogenesis of Campylobacter jejuni-associated Guillain-Barré syndrome (GBS) is not yet well established probably due to lack of experimental model. Therefore, we studied the Th1/Th2 immune response and pathological changes in C. jejuni-induced chicken model for GBS. C. jejuni (5 × 10(9) CFU/ml) and placebo were fed to 30 chickens each. Stools of all birds were negative for C. jejuni by culture and PCR before experiment. The birds were regularly assessed for disease symptoms up to 30 days. Sciatic nerves from all chickens were examined at 5 days intervals by histopathology and immunohistochemistry, and also for the expression of Th1/Th2 cytokines. Twenty-two chickens (73.3%) developed diarrhea after C. jejuni infection; 18 (60.0%) experimental chickens developed GBS-like paralytic neuropathy. Pathology in the sciatic nerves of these chickens included perinodal and/or patchy demyelination, perivascular focal lymphocytic infiltration, myelin swelling and presence of macrophages within the nerve fibers on 10th-20th post-infection day (PID). Cytokines (IFN-γ, IL-1β, TNF-α, IL-6 and IL-2) were elevated in early phase (5th-15th PID) and TGF-β2, IL-10 and IL-4 in the recovery phase (25th-30th PID) of the disease. The study provides evidence that C. jejuni infection in the chicken can provide an experimental animal model of GBS.

  12. Co-existence of Echinococcus granulosus infection and cancer metastasis in the liver correlates with reduced Th1 immune responses.

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    Turhan, N; Esendagli, G; Ozkayar, O; Tunali, G; Sokmensuer, C; Abbasoglu, O

    2015-01-01

    A possible relationship between cancer and Echinococcus granulosus infection has been postulated. As T cells are critical players in immune responses against both infections and malignancies, in an experimental model of secondary echinococcosis and breast cancer, this study aims to observe the progression of cancer and to determine the characters of T-cell responses. 4T1 breast tumour cells were subcutaneously injected into mammary region, whereas protoscoleces were intraperitoneally inoculated into the mice. Hydatid cysts, tumours and metastases were determined with macroscopic and histopathological evaluation. T cells found in spleen, liver and tumour were characterised by flow cytometric analysis of CD3, CD4, CD8, CD25, CCR5, CCR3, IL-4 and IFN-γ. In the mice inoculated both with protoscoleces and with breast tumour cells, increased frequency of cancer metastasis was observed in the liver. The amount of CD4(+) T cells was increased in the liver and in the spleen of mice infected with E. granulosus. However, co-existence of echinococcosis and metastatic lesions in the liver was associated with significant reduction in the IFN-γ(+) and CCR5(+) Th1 cells and increase in the CD25(+) T cells. Our results may indicate an immunological link between cystic echinococcosis and cancer that allows tumour metastasis to flourish in the liver. © 2014 John Wiley & Sons Ltd.

  13. Epitope based recombinant BCG vaccine elicits specific Th1 polarized immune responses in BALB/c mice.

    Science.gov (United States)

    Christy, Aparna Josephine; Dharman, Karthika; Dhandapaani, Gayatri; Palaniyandi, Kannan; Gupta, Umesh D; Gupta, Pushpa; Ignacimuthu, S; Narayanan, Sujatha

    2012-02-08

    Developing an efficacious vaccine is one of the highest priorities in tuberculosis research. A vaccine based on T cell epitopes representing multiple antigens is an ideal approach to generate effective cellular immunity against the disease. In the present study, we have selected four T cell epitopes from four well defined Mycobacterium tuberculosis antigens, Ag85C (Rv2903c), 10-kDa culture filtrate protein (CFP-10) (Rv3874), PPE68 (Rv3873) and INV (Rv1478). The epitope encoding genes were grafted into a Cpn 10 based epitope delivery system. The cpn 10-epitope chimeras were further cloned and expressed in BCG to obtain four rBCGs (BCG::CFP, BCG::FBP, BCG::PPE and BCG::INV). Both cellular and humoral immune responses induced by these r-BCG strains were evaluated in BALB/c mice after subcutaneous injection of a single dose of 1×10(6)CFU of the individual rBCGs. Compared to the parent BCG immunized animals the splenocytes derived from rBCG vaccinated groups showed greater antigen specific proliferation, characterized with higher IFN-γ response and reduced IL-4 secretion. Also rBCG vaccination was able to induce specific humoral immune response with an enhanced IgG2a/IgG1 ratio. The rBCGs therefore favor an epitope specific Th1 type response, which is known to be important for mycobacterial immunity. Further when two of the rBCGs (BCG::CFP and BCG::FBP) were tested for their protective efficacy both the rBCGs were comparable to BCG in a H37Rv challenge study performed in guinea pigs. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Increased Th1/Th17 Responses Contribute to Low-Grade Inflammation in Age-Related Macular Degeneration.

    Science.gov (United States)

    Chen, Jiajia; Wang, Wenzhan; Li, Qiuming

    2017-01-01

    Age-related macular degeneration (AMD) is the primary cause of senior blindness in developed countries. Mechanisms underlying initiation and development of AMD remained known. We examined the CD4+ T cell compartments and their functions in AMD patients. AMD patients presented significantly higher frequencies of interferon (IFN)-γ-expressing and interleukin (IL)-17-expressing CD4+ T cells than healthy controls. The levels of IFN-γ and IL-17 expression by CD4+ T cells were significantly higher in AMD patients. These IFN-γ-expressing Th1 cells and IL-17-expressing Th17 cells could be selectively enriched by surface CCR3+ and CCR4+CCR6+ expression, respectively. Th1 and Th17 cells from AMD patients promoted the differentiation of monocytes toward M1 macrophages, which were previously associated with retinal damage. Th1 and Th17 cells also increased the level of MHC class I expression in human retinal pigment epithelial (RPE)-1 cells, while Th1 cells increased the frequency of MHC class II-expressing RPE-1 cells. These proinflammatory effects were partly, but not entirely, induced by the secretion of IFN-γ and IL-17. This study demonstrated an enrichment of Th1 cells and Th17 cells in AMD patients. These Th1 and Th17 cells possessed proinflammatory roles in an IFN-γ- and IL-17-dependent fashion, and could potentially serve as therapeutic targets. © 2017 The Author(s). Published by S. Karger AG, Basel.

  15. Increased Th1/Th17 Responses Contribute to Low-Grade Inflammation in Age-Related Macular Degeneration

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    Jiajia Chen

    2017-11-01

    Full Text Available Background/Aims: Age-related macular degeneration (AMD is the primary cause of senior blindness in developed countries. Mechanisms underlying initiation and development of AMD remained known. Methods: We examined the CD4+ T cell compartments and their functions in AMD patients. Results: AMD patients presented significantly higher frequencies of interferon (IFN-γ-expressing and interleukin (IL-17-expressing CD4+ T cells than healthy controls. The levels of IFN-γ and IL-17 expression by CD4+ T cells were significantly higher in AMD patients. These IFN-γ-expressing Th1 cells and IL-17-expressing Th17 cells could be selectively enriched by surface CCR3+ and CCR4+CCR6+ expression, respectively. Th1 and Th17 cells from AMD patients promoted the differentiation of monocytes toward M1 macrophages, which were previously associated with retinal damage. Th1 and Th17 cells also increased the level of MHC class I expression in human retinal pigment epithelial (RPE-1 cells, while Th1 cells increased the frequency of MHC class II-expressing RPE-1 cells. These proinflammatory effects were partly, but not entirely, induced by the secretion of IFN-γ and IL-17. Conclusions: This study demonstrated an enrichment of Th1 cells and Th17 cells in AMD patients. These Th1 and Th17 cells possessed proinflammatory roles in an IFN-γ- and IL-17-dependent fashion, and could potentially serve as therapeutic targets.

  16. The systemic immune state of super-shedder mice is characterized by a unique neutrophil-dependent blunting of TH1 responses.

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    Smita Gopinath

    Full Text Available Host-to-host transmission of a pathogen ensures its successful propagation and maintenance within a host population. A striking feature of disease transmission is the heterogeneity in host infectiousness. It has been proposed that within a host population, 20% of the infected hosts, termed super-shedders, are responsible for 80% of disease transmission. However, very little is known about the immune state of these super-shedders. In this study, we used the model organism Salmonella enterica serovar Typhimurium, an important cause of disease in humans and animal hosts, to study the immune state of super-shedders. Compared to moderate shedders, super-shedder mice had an active inflammatory response in both the gastrointestinal tract and the spleen but a dampened T(H1 response specific to the secondary lymphoid organs. Spleens from super-shedder mice had higher numbers of neutrophils, and a dampened T cell response, characterized by higher levels of regulatory T cells (T(regs, fewer T-bet(+ (T(H1 T cells as well as blunted cytokine responsiveness. Administration of the cytokine granulocyte colony stimulating factor (G-CSF and subsequent neutrophilia was sufficient to induce the super-shedder immune phenotype in moderate-shedder mice. Similar to super-shedders, these G-CSF-treated moderate-shedders had a dampened T(H1 response with fewer T-bet(+ T cells and a loss of cytokine responsiveness. Additionally, G-CSF treatment inhibited IL-2-mediated TH1 expansion. Finally, depletion of neutrophils led to an increase in the number of T-bet(+ T(H1 cells and restored their ability to respond to IL-2. Taken together, we demonstrate a novel role for neutrophils in blunting IL-2-mediated proliferation of the TH1 immune response in the spleens of mice that are colonized by high levels of S. Typhimurium in the gastrointestinal tract.

  17. Polysaccharides from Ganoderma formosanum function as a Th1 adjuvant and stimulate cytotoxic T cell response in vivo.

    Science.gov (United States)

    Pi, Chia-Chen; Chu, Ching-Liang; Lu, Chu-Ying; Zhuang, Yu-Jing; Wang, Cheng-Li; Yu, Yao-Hsuan; Wang, Hui-Yi; Lin, Chih-Chung; Chen, Chun-Jen

    2014-01-09

    The fungus of Ganoderma is a basidiomycete that possesses a variety of pharmacological effects and has been used in traditional Asian medicine for centuries. Ganoderma formosanum is a native Ganoderma species isolated in Taiwan, and we have previously demonstrated that PS-F2, a polysaccharide fraction purified from the submerged culture broth of G. formosanum, exhibits immunostimulatory properties in macrophages. In this study, we further characterized the adjuvant functions of PS-F2. In vitro, PS-F2 stimulated dendritic cells (DCs) to produce proinflammatory cytokines, including TNF-α, interleukin (IL)-6, and IL-12/IL-23 p40. PS-F2 also stimulated DCs to express the maturation markers CD40, CD80, CD86, and MHC class II. In a murine splenocyte culture, PS-F2 treatment resulted in elevated expression of T-bet and interferon (IFN)-γ in T lymphocytes. When used as an adjuvant in vivo with the ovalbumin (OVA) antigen, PS-F2 stimulated OVA-specific antibody production and primed IFN-γ production in OVA-specific T lymphocytes. PS-F2-adjuvated immunization also induced OVA-specific CTLs, which protected mice from a challenge with tumor cells expressing OVA. Collectively, our data show that PS-F2 functions as an adjuvant capable of inducing a Th1-polarized adaptive immune response, which would be useful in vaccines against viruses and tumors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. A Schistosoma japonicum chimeric protein with a novel adjuvant induced a polarized Th1 immune response and protection against liver egg burdens

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    Xue Xiangyang

    2009-05-01

    Full Text Available Abstract Background Schitosomiasis japonica is still a significant public health problem in China. A protective vaccine for human or animal use represents an important strategy for long-term control of this disease. Due to the complex life cycle of schistosomes, different vaccine design approaches may be necessary, including polyvalent subunit vaccines. In this study, we constructed four chimeric proteins (designated SjGP-1~4 via fusion of Sj26GST and four individual paramyosin fragments. We tested these four proteins as vaccine candidates, and investigated the effect of deviating immune response on protection roles in mice. Methods The immunogencity and protection efficacy of chimeric proteins were evaluated in mice. Next, the chimeric protein SjGP-3 was selected and formulated in various adjuvants, including CFA, ISA 206, IMS 1312 and ISA 70M. The titers of antigen-specific IgG, IgE and IgG subclass were measured. The effect of adjuvant on cytokine production and percentages of CD3+CD8-IFN-γ+ cells and CD3+CD8-IL-4+ cells were analyzed at different time points. Worm burdens and liver egg counts in different adjuvant groups were counted to evaluate the protection efficacy against cercarial challenge. Results Immunization of mice with chimeric proteins provided various levels of protection. Among the four proteins, SjGP-3 induced the highest level of protection, and showed enhanced protective efficacy compared with its individual component Sj26GST. Because of this, SjGP-3 was further formulated in various adjuvants to investigate the effect of adjuvant on immune deviation. The results revealed that SjGP-3 formulated in veterinary adjuvant ISA 70M induced a lasting polarized Th1 immune response, whereas the other adjuvants, including CFA, ISA 206 and IMS 1312, generated a moderate mixed Th1/Th2 response after immunization but all except for IMS 1312 shifted to Th2 response after onset of eggs. More importantly, the SjGP-3/70M formulation induced

  19. Interferon-γ Added During Bacillus Calmette-Guerin Induced Dendritic Cell Maturation Stimulates Potent Th1 Immune Responses

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    Pestano Linda A

    2003-10-01

    Full Text Available Abstract Dendritic cells (DC are increasingly prepared in vitro for use in immunotherapy trials. Mature DC express high levels of surface molecules needed for T cell activation and are superior at antigen-presentation than immature DC. Bacillus Calmette-Guerin (BCG is one of several products known to induce DC maturation, and interferon (IFN-γ has been shown to enhance the activity of DC stimulated with certain maturation factors. In this study, we investigated the use of IFN-γ in combination with the powerful maturation agent, BCG. The treatment of immature DC with IFN-γ plus BCG led to the upregulation of CD54, CD80, and CD86 in comparison with BCG treatment alone. In MLR or recall immune responses, the addition of IFN-γ at the time of BCG-treatment did not increase the number of antigen-specific T cells but enhanced the development of IFN-γ-producing Th1 cells. In primary immune responses, on the other hand, BCG and IFN-γ co-treated DC stimulated higher proportions of specific T cells as well as IFN-γ secretion by these T cells. Thus the use of IFN-γ during BCG-induced DC maturation differentially affects the nature of recall versus naïve antigen-specific T-cell responses. IFN-γ co-treatment with BCG was found to induce IL-12 and, in some instances, inhibit IL-10 secretion by DC. These findings greatly enhance the potential of BCG-matured dendritic cells for use in cancer immunotherapy.

  20. Paradoxical Expansion of Th1 and Th17 Lymphocytes in Rheumatoid Arthritis Following Infliximab Treatment: a Possible Explanation for a Lack of Clinical Response.

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    Talotta, Rossella; Berzi, Angela; Atzeni, Fabiola; Batticciotto, Alberto; Clerici, Mario; Sarzi-Puttini, Piercarlo; Trabattoni, Daria

    2015-08-01

    The immunogenicity of anti-TNF-α drugs may affect their safety and efficacy. Infliximab (IFX), a chimeric monoclonal antibody, induces antibody formation in up to 60% of cases. Some studies have suggested the involvement of a Th1 response to TNFα blockers following immunization, but the triggering of Th17 responses has never been reported. The aim of this study is to investigate whether the immunogenicity of IFX affects the Th1, Th17 and Treg compartments in rheumatoid arthritis (RA) patients failing IFX therapy, and verify whether this may be responsible for treatment failure. The study involved 55 patients with RA (15 treatment-naïve patients; 20 IFX responders; 20 IFX non-responders) and 10 healthy controls. PBMCs were cultured in the presence/absence of IFX, and the variations in the percentage of Th1, Th17 and Treg lymphocytes following IFX treatment were analysed. IFX-specific Th1 and Th17 responses and an increase in IL-21 production were observed in patients failing IFX (p < 0.01, p < 0.05, and p < 0.01 respectively). In contrast, IFX incubation reduced significantly Th1 and Th17 responses and IL-21 production (p < 0.05) in successfully-treated subjects, but did not affect these responses in healthy controls or treatment-naïve patients. RA patients may have impaired peripheral tolerance, which could favour the development of an aberrant immunological response to biological drugs. The loss of therapeutic effectiveness of IFX and the onset of adverse events may be due to a paradoxical activation of Th17 or Th1 lymphocytes following sensitisation, thus worsening the patients' inflammatory status.

  1. The combination of early and rapid type I IFN, IL-1α, and IL-1β production are essential mediators of RNA-like adjuvant driven CD4+ Th1 responses.

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    Rachel F Madera

    Full Text Available There is a growing need for novel vaccine adjuvants that can provide safe and potent T-helper type 1 (Th1 activity. RNA-like immune response modifiers (IRMs are candidate T-cell adjuvants that skew acquired immune responses towards a Th1 phenotype. We set out to delineate the essential signaling pathways by which the RNA-like IRMs, resiquimod (R-848 and polyinosinic:polycytidylic acid (poly I:C, augment CD4+ T-helper 1 (Th1 responses. Highly purified murine conventional dendritic cells (cDCs and conventional CD4+ T-cells were co-cultured in allogeneic and MHC congenic mixed leukocyte reactions. The activation of CD4+ Th1 cells was examined utilizing cells from mice deficient in specific RNA-sensing pattern recognition receptors and signaling mediators. R-848 and poly I:C stimulation of Type I interferon production and signaling in cDCs was essential but not sufficient for driving CD4+ Th1 responses. The early and rapid production of IL-1α and IL-1β was equally critical for the optimal activation of Th1 CD4+ T-cells. R-848 activation of Toll-like receptor 7/MyD88-dependent signaling in cDCs led to a rapid upregulation of pro-IL-1α and pro-IL-1β production compared to poly I:C activation of MyD88-independent signaling pathways. The in vitro data show that CD4+ T-cell adjuvant activity of RNA-like IRMs is mediated by a critical combination of early and rapid Type I interferon, IL-1α and IL-1β production. These results provide important insights into the key signaling pathways responsible for RNA-like IRM CD4+ Th1 activation. A better understanding of the critical signaling pathways by which RNA-like IRMs stimulate CD4+ Th1 responses is relevant to the rational design of improved vaccine adjuvants.

  2. Characterization of onion lectin (Allium cepa agglutinin) as an immunomodulatory protein inducing Th1-type immune response in vitro.

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    Prasanna, Vaddi K; Venkatesh, Yeldur P

    2015-06-01

    Onion (Allium cepa), a bulb crop of economic importance, is known to have many health benefits. The major objective of the present study is to address the immunomodulatory properties of onion lectin (A. cepa agglutinin; ACA). ACA was purified from onion extract by D-mannose-agarose chromatography (yield: ~1 mg/kg). ACA is non-glycosylated and showed a molecular mass of ~12 kDa under reducing/non-reducing SDS-PAGE; glutaraldehyde cross-linking indicated that ACA is a non-covalent tetramer of ~12 kDa subunits. Its N-terminal sequence (RNVLLNNEGL; UniProt KB Accn. C0HJM8) showed 70-90% homology to mannose-specific Allium agglutinins. ACA showed specific hemagglutination activity of 8200 units/mg and is stable in the pH range 6-10 and up to 45° C. The immunomodulatory activity of ACA was assessed using the macrophage cell line, RAW264.7 and rat peritoneal macrophages; at 0.1 μg/well, it showed a significant increase (6-8-fold vs. control) in the production of nitric oxide at 24h, and significantly stimulated (2-4-fold vs. control) the production of pro-inflammatory cytokines (TNF-α and IL-12) at 24h. ACA (0.1 μg/well) enhanced the proliferation of murine thymocytes by ~4 fold (vs. control) at 24h; however, ACA does not proliferate B cell-enriched rat splenocytes. Further, it significantly elevated the expression levels of cytokines (IFN-γ and IL-2) over the control in murine thymocytes. Taken together, purified ACA induces a Th1-type immune response in vitro. Though present in low amounts, ACA may contribute to the immune-boosting potential of the popular spice onion since considerable amounts are consumed on a daily basis universally. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Neisseria gonorrhoeae selectively suppresses the development of Th1 and Th2 cells, and enhances Th17 cell responses, through TGF-β-dependent mechanisms

    Science.gov (United States)

    Liu, Yingru; Islam, Epshita A.; Jarvis, Gary A.; Gray-Owen, Scott D.; Russell, Michael W.

    2012-01-01

    Infection with Neisseria gonorrhoeae does not induce specific immunity or immune memory. Our previous studies in a murine model of vaginal gonococcal infection showed that innate immunity governed by Th17 cells was a critical aspect of the immune response elicited by this pathogen. Herein we show that N. gonorrhoeae selectively inhibited Th1 and Th2 cells and enhanced Th17 cell development through the induction of TGF-β. Whereas Th17 responses depended on gonococcal lipooligosaccharide acting through TLR4, the inhibitory effect of N. gonorrhoeae on Th1/Th2 responses involved gonococcal Opa proteins. In vitro Th17 responses to N. gonorrhoeae could be diverted to Th1/Th2 by blockade of TGF-β, but not by blockade of IL-17. The results reveal that N. gonorrhoeae suppresses Th1/Th2-mediated adaptive immune response through mechanisms dependent on TGF-β, and that this effect can be manipulated to promote the development of adaptive immunity. PMID:22354319

  4. BCG dose reduction by decreasing the instillation frequency: Effects on local Th1/Th2 cytokine responses in a mouse model

    NARCIS (Netherlands)

    de Boer, Elizabeth C.; Rooyakkers, Sietske J.; Schamhart, Denis H. J.; de Reijke, Theo M.; Kurth, Karl-Heinz

    2005-01-01

    Objectives: Based on the requirement of a Th1 immune response for clinical efficacy, and incited by the arbitrary induction scheme, frequent side effects and the empirical approach in improving BCG immunotherapy for superficial bladder cancer, an alternative intravesical BCG treatment schedule for

  5. Experimental autoimmune myasthenia gravis may occur in the context of a polarized Th1- or Th2-type immune response in rats

    DEFF Research Database (Denmark)

    Saoudi, A; Bernard, I; Hoedemaekers, A

    1999-01-01

    Experimental autoimmune myasthenia gravis (EAMG) is a T cell-dependent, Ab-mediated autoimmune disease induced in rats by a single immunization with acetylcholine receptor (AChR). Although polarized Th1 responses have been shown to be crucial for the development of mouse EAMG, the role of Th cell...

  6. Cytokine gene expression in a mouse model: The first instillations with viable bacillus Calmette-Guerin determine the succeeding Th1 response

    NARCIS (Netherlands)

    de Boer, Elizabeth C.; Rooijakkers, Sietske J.; Schamhart, Denis H.; Kurth, Karl-Heinz

    2003-01-01

    Purpose: Bacillus Calmette-Guerin (BCG) therapy for superficial bladder cancer is immune dependent and activation of a Th1 immune response is probably required for clinical efficacy. Given the empirical approach to improving BCG therapy we investigated in a mouse model the consequences of

  7. The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo

    DEFF Research Database (Denmark)

    Kishimoto, K; Dong, V M; Issazadeh-Navikas, Shohreh

    2000-01-01

    We used signal transducer and activator of transcription 4 (STAT4) and STAT6 gene knockout (-/-) mice as recipients of fully mismatched cardiac allografts to study the role of T-cell costimulatory pathways in regulating allogeneic T-helper 1 (Th1) versus Th2 responses in vivo. STAT4(-/-) mice hav...

  8. Th1 immune response to H. pylori infection varies according to the age of the patients and influences the gastric inflammatory patterns.

    Science.gov (United States)

    Freire de Melo, Fabrício; Rocha, Gifone Aguiar; Rocha, Andreia Maria Camargos; Teixeira, Kádima Nayara; Pedroso, Silvia Helena Souza Pietra; Pereira Junior, João Bosco; Fonseca de Castro, Lúcia Porto; Cabral, Mônica Maria Demas Álvares; Carvalho, Simone Diniz; Bittencourt, Paulo Fernando Souto; de Oliveira, Celso Afonso; Queiroz, Dulciene Maria de Magalhães

    2014-05-01

    To compare children and adults in respect to the effect of H. pylori infection on the gastric concentrations of cytokines linked to innate and Th1 immune response, as well as to investigate the changes in the gastric concentrations of the studied cytokines according to the age. We studied 245 children (142 H. pylori-negative and 103 H. pylori-positive) and 140 adults (40 H. pylori-negative and 100 H. pylori-positive). The gastric concentrations of cytokines representative of the innate and Th1 response were higher in the H. pylori-positive than in the -negative children and adults. The gastric concentrations of IL-1α and TNF-α were significantly higher, while those of IL-2, IL-12p70 and IFN-γ were lower in the infected children than in the infected adults. In the infected children, the gastric concentration of IL-1α, IL-2, IL-12p70 and IFN-γ increased, whereas in adults, the gastric concentrations of IFN-γ and IL-12p70 decreased with the aging. Increased gastric concentration of Th1 associated cytokines correlated with increased degree of gastritis that is the background lesion for the development of the H. pylori associated severe diseases. Concluding, Th1 response to H. pylori infection varies according to the age and seems to have determinant implication in the H. pylori infection outcomes. Copyright © 2013 Elsevier GmbH. All rights reserved.

  9. Intratumoral Th2 predisposition combines with an increased Th1 functional phenotype in clinical response to intravesical BCG in bladder cancer.

    Science.gov (United States)

    Pichler, Renate; Gruenbacher, Georg; Culig, Zoran; Brunner, Andrea; Fuchs, Dietmar; Fritz, Josef; Gander, Hubert; Rahm, Andrea; Thurnher, Martin

    2017-04-01

    Th1-type immunity is considered to be required for efficient response to BCG in bladder cancer, although Th2 predisposition of BCG responders has recently been reported. The aim was to evaluate the relationship of Th1 and Th2 components in 23 patients undergoing BCG treatment. Peripheral blood, serum and urine samples were prospectively collected at baseline, during and after BCG. Th1 (neopterin, tryptophan, kynurenine, kynurenine-to-tryptophan ratio (KTR), IL-12, IFN-γ, soluble TNF-R75 and IL-2Rα) and Th2 (IL-4, IL-10) biomarkers as well as CD4 expression in T helper (Th), effector and regulatory T cells were determined. Local immune cell subsets were measured on formalin-fixed, paraffin-embedded cancer tissue by immunohistochemistry to examine expression of transcription factors that control Th1 (T-bet) and Th2-type (GATA3) immunity. We confirmed a Th2 predisposition with a mean GATA3/T-bet ratio of 5.51. BCG responders showed significantly higher levels of urinary (p = 0.003) and serum neopterin (p = 0.012), kynurenine (p = 0.015), KTR (p = 0.005), IFN-γ (p = 0.005) and IL-12 (p = 0.003) during therapy, whereas levels of IL-10 decreased significantly (p BCG instillation. We observed a significant increase in CD4 expression in the Th cell population (p BCG response. Th2-promoting factors such as GATA3 may trigger Th1-type immune responses and thus contribute to the BCG success.

  10. Immunization with Brucella VirB proteins reduces organ colonization in mice through a Th1-type immune response and elicits a similar immune response in dogs.

    Science.gov (United States)

    Pollak, Cora N; Wanke, María Magdalena; Estein, Silvia M; Delpino, M Victoria; Monachesi, Norma E; Comercio, Elida A; Fossati, Carlos A; Baldi, Pablo C

    2015-03-01

    VirB proteins from Brucella spp. constitute the type IV secretion system, a key virulence factor mediating the intracellular survival of these bacteria. Here, we assessed whether a Th1-type immune response against VirB proteins may protect mice from Brucella infection and whether this response can be induced in the dog, a natural host for Brucella. Splenocytes from mice immunized with VirB7 or VirB9 responded to their respective antigens with significant and specific production of gamma interferon (IFN-γ), whereas interleukin-4 (IL-4) was not detected. Thirty days after an intraperitoneal challenge with live Brucella abortus, the spleen load of bacteria was almost 1 log lower in mice immunized with VirB proteins than in unvaccinated animals. As colonization reduction seemed to correlate with a Th1-type immune response against VirB proteins, we decided to assess whether such a response could be elicited in the dog. Peripheral blood mononuclear cells (PBMCs) from dogs immunized with VirB proteins (three subcutaneous doses in QuilA adjuvant) produced significantly higher levels of IFN-γ than cells from control animals upon in vitro stimulation with VirB proteins. A skin test to assess specific delayed-type hypersensitivity was positive in 4 out of 5 dogs immunized with either VirB7 or VirB9. As both proteins are predicted to locate in the outer membrane of Brucella organisms, the ability of anti-VirB antibodies to mediate complement-dependent bacteriolysis of B. canis was assessed in vitro. Sera from dogs immunized with either VirB7 or VirB9, but not from those receiving phosphate-buffered saline (PBS), produced significant bacteriolysis. These results suggest that VirB-specific responses that reduce organ colonization by Brucella in mice can be also elicited in dogs. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  11. Caribbean and La Réunion Chikungunya Virus Isolates Differ in Their Capacity To Induce Proinflammatory Th1 and NK Cell Responses and Acute Joint Pathology.

    Science.gov (United States)

    Teo, Teck-Hui; Her, Zhisheng; Tan, Jeslin J L; Lum, Fok-Moon; Lee, Wendy W L; Chan, Yi-Hao; Ong, Ruo-Yan; Kam, Yiu-Wing; Leparc-Goffart, Isabelle; Gallian, Pierre; Rénia, Laurent; de Lamballerie, Xavier; Ng, Lisa F P

    2015-08-01

    Chikungunya virus (CHIKV) is a mosquito-borne arthralgic alphavirus that has garnered international attention as an important emerging pathogen since 2005. More recently, it invaded the Caribbean islands and the Western Hemisphere. Intriguingly, the current CHIKV outbreak in the Caribbean is caused by the Asian CHIKV genotype, which differs from the La Réunion LR2006 OPY1 isolate belonging to the Indian Ocean lineage. Here, we adopted a systematic and comparative approach against LR2006 OPY1 to characterize the pathogenicity of the Caribbean CNR20235 isolate and consequential host immune responses in mice. Ex vivo infection using primary mouse tail fibroblasts revealed a weaker replication efficiency by CNR20235 isolate. In the CHIKV mouse model, CNR20235 infection induced an enervated joint pathology characterized by moderate edema and swelling, independent of mononuclear cell infiltration. Based on systemic cytokine analysis, localized immunophenotyping, and gene expression profiles in the popliteal lymph node and inflamed joints, two pathogenic phases were defined for CHIKV infection: early acute (2 to 3 days postinfection [dpi]) and late acute (6 to 8 dpi). Reduced joint pathology during early acute phase of CNR20235 infection was associated with a weaker proinflammatory Th1 response and natural killer (NK) cell activity. The pathological role of NK cells was further demonstrated as depletion of NK cells reduced joint pathology in LR2006 OPY1. Taken together, this study provides evidence that the Caribbean CNR20235 isolate has an enfeebled replication and induces a less pathogenic response in the mammalian host. The introduction of CHIKV in the Americas has heightened the risk of large-scale outbreaks due to the close proximity between the United States and the Caribbean. The immunopathogenicity of the circulating Caribbean CHIKV isolate was explored, where it was demonstrated to exhibit reduced infectivity resulting in a weakened joint pathology. Analysis of

  12. Babassu aqueous extract (BAE as an adjuvant for T helper (Th1-dependent immune responses in mice of a Th2 immune response-prone strain

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    Nascimento Flavia RF

    2011-01-01

    Full Text Available Abstract Background The aqueous extract of a Brazilian palm-tree fruit - the babassu - (BAE exerts a clear immunostimulative activity in vivo. In the present work, the possibility that BAE can promote Th1 immune responses in mice of a Th2 immune response-prone strain - the BALB/c was investigated. BAE itself, and preparations consisting of Leishmania amazonensis promastigote extract (LE, adsorbed or not to Al(OH3, and in the presence or not of BAE, were used as immunogens. LE and Al(OH3 have been shown to preferentially elicit Th2 immune responses. Results The addition of BAE to LE-containing immunogenic preparations, adsorbed or not to Al(OH3, clearly promoted the in vitro production of interferon γ (IFN-γ, a major Th1-dependent cytokine, and not of interleukin (IL-4 (a Th2-dependent cytokine, by LE-stimulated splenocytes of immunized BALB/c mice. It also promoted the in vivo formation of IgG2a anti-LE antibodies. However, immunization with LE by itself led to an increased production of IL-4 by LE-stimulated splenocytes, and this production, albeit not enhanced, was not reduced by the addition of BAE to the immunogen. On the other hand, the IL-4 production by LE-stimulated splenocytes was significantly lower in mice immunized with a preparation containing Al(OH3-adsorbed LE and BAE than in mice immunized with the control preparation of Al(OH3-adsorbed LE without BAE. Moreover, an increased production of IFN-γ, and not of IL-4, was observed in the culture supernatants of splenocytes, from BAE-immunized mice, which were in vitro stimulated with BAE or which received no specific in vitro stimulus. No differences in IL-10 (an immunoregulatory cytokine levels in the supernatants of splenocytes from mice that were injected with BAE, in relation to splenocytes from control mice, were observed. The spontaneous ex vivo production of NO by splenocytes of mice that had been injected with BAE was significantly higher than the production of NO by

  13. The Mincle-activating adjuvant TDB induces MyD88-dependent Th1 and Th17 responses through IL-1R signaling.

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    Christiane Desel

    Full Text Available Successful vaccination against intracellular pathogens requires the generation of cellular immune responses. Trehalose-6,6-dibehenate (TDB, the synthetic analog of the mycobacterial cord factor trehalose-6,6-dimycolate (TDM, is a potent adjuvant inducing strong Th1 and Th17 immune responses. We previously identified the C-type lectin Mincle as receptor for these glycolipids that triggers the FcRγ-Syk-Card9 pathway for APC activation and adjuvanticity. Interestingly, in vivo data revealed that the adjuvant effect was not solely Mincle-dependent but also required MyD88. Therefore, we dissected which MyD88-dependent pathways are essential for successful immunization with a tuberculosis subunit vaccine. We show here that antigen-specific Th1/Th17 immune responses required IL-1 receptor-mediated signals independent of IL-18 and IL-33-signaling. ASC-deficient mice had impaired IL-17 but intact IFNγ responses, indicating partial independence of TDB adjuvanticity from inflammasome activation. Our data suggest that the glycolipid adjuvant TDB triggers Mincle-dependent IL-1 production to induce MyD88-dependent Th1/Th17 responses in vivo.

  14. Effects of intestinal bacteria-derived p-cresyl sulfate on Th1-type immune response in vivo and in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Shiba, Takahiro, E-mail: takahiro-shiba@yakult.co.jp; Kawakami, Koji; Sasaki, Takashi; Makino, Ikuyo; Kato, Ikuo; Kobayashi, Toshihide; Uchida, Kazumi; Kaneko, Kimiyuki

    2014-01-15

    Protein fermentation by intestinal bacteria generates various compounds that are not synthesized by their hosts. An example is p-cresol, which is produced from tyrosine. Patients with chronic kidney disease (CKD) accumulate high concentrations of intestinal bacteria-derived p-cresyl sulfate (pCS), which is the major metabolite of p-cresol, in their blood, and this accumulation contributes to certain CKD-associated disorders. Immune dysfunction is a CKD-associated disorder that frequently contributes to infectious diseases among CKD patients. Although some studies imply pCS as an etiological factor, the relation between pCS and immune systems is poorly understood. In the present study, we investigated the immunological effects of pCS derived from intestinal bacteria in mice. For this purpose, we fed mice a tyrosine-rich diet that causes the accumulation of pCS in their blood. The mice were shown to exhibit decreased Th1-driven 2, 4-dinitrofluorobenzene-induced contact hypersensitivity response. The concentration of pCS in blood was negatively correlated with the degree of the contact hypersensitivity response. In contrast, the T cell-dependent antibody response was not influenced by the accumulated pCS. We also examined the in vitro cytokine responses by T cells in the presence of pCS. The production of IFN-γ was suppressed by pCS. Further, pCS decreased the percentage of IFN-γ-producing Th1 cells. Our results suggest that intestinal bacteria-derived pCS suppressesTh1-type cellular immune responses. - Highlights: • Mice fed a tyrosine-rich diet accumulated p-cresyl sulfate in their blood. • p-Cresyl sulfate negatively correlated with contact hypersensitivity response. • The in vitro production of IFN-γ was suppressed by p-cresyl sulfate. • p-Cresyl sulfate decreased the percentage of IFN-γ-producing Th1 cells in vitro.

  15. CryJ-LAMP DNA Vaccines for Japanese Red Cedar Allergy Induce Robust Th1-Type Immune Responses in Murine Model

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    Yan Su

    2016-01-01

    Full Text Available Allergies caused by Japanese Red Cedar (JRC pollen affect up to a third of Japanese people, necessitating development of an effective therapeutic. We utilized the lysosomal targeting property of lysosomal-associated membrane protein-1 (LAMP-1 to make DNA vaccines that encode LAMP-1 and the sequences of immunodominant allergen CryJ1 or CryJ2 from the JRC pollen. This novel strategy is designed to skew the CD4 T cell responses to the target allergens towards a nonallergenic Th1 response. CryJ1-LAMP and CryJ2-LAMP were administrated to BALB/c mice and antigen-specific Th1-type IgG2a and Th2-type IgG1 antibodies, as well as IgE antibodies, were assayed longitudinally. We also isolated different T cell populations from immunized mice and adoptively transferred them into naïve mice followed by CryJ1/CryJ2 protein boosts. We demonstrated that CryJ-LAMP immunized mice produce high levels of IFN-γ and anti-CryJ1 or anti-CryJ2 IgG2a antibodies and low levels of IgE antibodies, suggesting that a Th1 response was induced. In addition, we found that CD4+ T cells are the immunological effectors of DNA vaccination in this allergy model. Together, our results suggest the CryJ-LAMP Vaccine has a potential as an effective therapeutic for JRC induced allergy by skewing Th1/Th2 responses.

  16. A Novel Prime and Boost Regimen of HIV Virus-Like Particles with TLR4 Adjuvant MPLA Induces Th1 Oriented Immune Responses against HIV.

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    Ethan Poteet

    Full Text Available HIV virus-like particles (VLPs present the HIV envelope protein in its native conformation, providing an ideal vaccine antigen. To enhance the immunogenicity of the VLP vaccine, we sought to improve upon two components; the route of administration and the additional adjuvant. Using HIV VLPs, we evaluated sub-cheek as a novel route of vaccine administration when combined with other conventional routes of immunization. Of five combinations of distinct prime and boost sequences, which included sub-cheek, intranasal, and intradermal routes of administration, intranasal prime and sub-cheek boost (IN+SC resulted in the highest HIV-specific IgG titers among the groups tested. Using the IN+SC regimen we tested the adjuvant VesiVax Conjugatable Adjuvant Lipid Vesicles (CALV + monophosphoryl lipid A (MPLA at MPLA concentrations of 0, 7.5, 12.5, and 25 μg/dose in combination with our VLPs. Mice that received 12.5 or 25 μg/dose MPLA had the highest concentrations of Env-specific IgG2c (20.7 and 18.4 μg/ml respectively, which represents a Th1 type of immune response in C57BL/6 mice. This was in sharp contrast to mice which received 0 or 7.5 μg MPLA adjuvant (6.05 and 5.68 μg/ml of IgG2c respectively. In contrast to IgG2c, MPLA had minor effects on Env-specific IgG1; therefore, 12.5 and 25 μg/dose of MPLA induced the optimal IgG1/IgG2c ratio of 1.3. Additionally, the percentage of germinal center B cells increased significantly from 15.4% in the control group to 31.9% in the CALV + 25 μg MPLA group. These mice also had significantly more IL-2 and less IL-4 Env-specific CD8+ T cells than controls, correlating with an increased percentage of Env-specific central memory CD4+ and CD8+ T cells. Our study shows the strong potential of IN+SC as an efficacious route of administration and the effectiveness of VLPs combined with MPLA adjuvant to induce Env specific Th1-oriented HIV-specific immune responses.

  17. Bordetella pertussis commits human dendritic cells to promote a Th1/Th17 response through the activity of adenylate cyclase toxin and MAPK-pathways.

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    Giorgio Fedele

    Full Text Available The complex pathology of B. pertussis infection is due to multiple virulence factors having disparate effects on different cell types. We focused our investigation on the ability of B. pertussis to modulate host immunity, in particular on the role played by adenylate cyclase toxin (CyaA, an important virulence factor of B. pertussis. As a tool, we used human monocyte derived dendritic cells (MDDC, an ex vivo model useful for the evaluation of the regulatory potential of DC on T cell immune responses. The work compared MDDC functions after encounter with wild-type B. pertussis (BpWT or a mutant lacking CyaA (BpCyaA-, or the BpCyaA- strain supplemented with either the fully functional CyaA or a derivative, CyaA*, lacking adenylate cyclase activity. As a first step, MDDC maturation, cytokine production, and modulation of T helper cell polarization were evaluated. As a second step, engagement of Toll-like receptors (TLR 2 and TLR4 by B. pertussis and the signaling events connected to this were analyzed. These approaches allowed us to demonstrate that CyaA expressed by B. pertussis strongly interferes with DC functions, by reducing the expression of phenotypic markers and immunomodulatory cytokines, and blocking IL-12p70 production. B. pertussis-treated MDDC promoted a mixed Th1/Th17 polarization, and the activity of CyaA altered the Th1/Th17 balance, enhancing Th17 and limiting Th1 expansion. We also demonstrated that Th1 effectors are induced by B. pertussis-MDDC in the absence of IL-12p70 through an ERK1/2 dependent mechanism, and that p38 MAPK is essential for MDDC-driven Th17 expansion. The data suggest that CyaA mediates an escape strategy for the bacterium, since it reduces Th1 immunity and increases Th17 responses thought to be responsible, when the response is exacerbated, for enhanced lung inflammation and injury.

  18. Lower Baseline Germinal Center Activity and Preserved Th1 Immunity are Associated with Hepatitis B Vaccine Response in Treated HIV Infection

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    Robert M. Paris

    2017-03-01

    Full Text Available Background: Why HIV-infected individuals have poor responses to standard dose and schedule hepatitis B virus immunization is not well understood. Methods: We compared the serologic and cellular immune profiles of treated HIV-infected individuals with similar durations of infection and preserved CD4 counts (>350 cells/microliter by hepatitis B vaccine (HBV response before and after vaccination. Results: Similar levels of immune activation and plasma cytokine profile were found between non-responders and responders. The baseline plasma levels of CXCL-13, a surrogate of germinal center reactivity, were significantly lower in HBV responders compared to HBV non-responders and were a predictor of both vaccine response and titer. Furthermore, response to HBV vaccination was associated with a significantly higher frequency of circulating IgGhigh memory B cells post vaccination and preserved Th1 antigen-specific T-cell responses. Conclusions: Taken together, our data suggest that preserved Th1 responses are associated with hepatitis B vaccine response in treated HIV infection.

  19. Antibiotic resistance free plasmid DNA expressing LACK protein leads towards a protective Th1 response against Leishmania infantum infection.

    Science.gov (United States)

    Ramos, I; Alonso, A; Peris, A; Marcen, J M; Abengozar, M A; Alcolea, P J; Castillo, J A; Larraga, V

    2009-11-12

    Canine visceral leishmaniasis is a serious public health concern in the Mediterranean basin since dogs are the main Leishmania infantum reservoir. However, there is not a vaccination method in veterinary use in this area, and therefore the development of a vaccine against this parasite is essential for the possible control of the disease. Previous reports have shown the efficacy of heterologous prime-boost vaccination with the pCIneo plasmid and the poxvirus VV (both Western Reserve and MVA strains) expressing L. infantum LACK antigen against canine leishmaniasis. As pCIneo-LACK plasmid contains antibiotic resistance genes, its use as a profilactic method is not recommended. Hence, the antibiotic resistance gene free pORT-LACK plasmid is a more suitable tool for its use as a vaccine. Here we report the protective and immunostimulatory effect of the prime-boost pORT-LACK/MVA-LACK vaccination tested in a canine experimental model. Vaccination induced a reduction in clinical signs and in parasite burden in the liver, an induction of the Leishmania-specific T cell activation, as well as an increase of the expression of Th1 type cytokines in PBMC and target organs.

  20. Suppression of allergic reactions by dehulled adlay in association with the balance of TH1/TH2 cell responses.

    Science.gov (United States)

    Hsu, Hsin-Yi; Lin, Bi-Fong; Lin, Jin-Yuarn; Kuo, Ching-Chuan; Chiang, Wenchang

    2003-06-18

    Dehulled adlay is known as a natural Chinese medicine having antiallergic activity, although its mechanism remains unclear. This study examined the effects of dehulled adlay on antigen-specific antibody and cytokine production. Mice were immunized three times with ovalbumin (OVA) in alum adjuvant. It was found that oral administration of dehulled adlay in mice suppressed the production of IgE against OVA antigen. Serum anti-OVA IgG(2a) antibody levels were significantly increased in mice after oral administration of dehulled adlay. Furthermore, the production of IL-2 by OVA-stimulated splenocytes was augmented in dehulled adlay-fed mice. Although dehulled adlay had no effect on the serum anti-OVA IgG(1) antibody levels, it had a great capacity to reduce IL-5 secretion by means of OVA-stimulated splenocytes. Hydrothermal processes, including steaming and extrusion cooking, did not change the capacity of dehulled adlay to suppress IgE production. Three fractions of dehulled alday, including methanolic extract, warm water extract, and residue, were obtained. The methanolic extract exhibited the greatest capacity to reduce anti-OVA IgE production. These results suggest that dehulled adlay has a modulating ability to shift the balance from Th2 to Th1 dominance in the T cell mediated immune system and may be beneficial for the treatment of allergic disorders.

  1. Intracellular Targeting of CEA Results in Th1-Type Antibody Responses Following Intradermal Genetic Vaccination by a Needle-Free Jet Injection Device

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    Susanne Johansson

    2007-01-01

    Full Text Available The route and method of immunization, as well as the cellular localization of the antigen, can influence the generation of an immune response. In general, intramuscular immunization results in Th1 responses, whereas intradermal delivery of DNA by gene gun immunization often results in more Th2 responses. Here we investigate how altering the cellular localization of the tumor antigen CEA (carcinoembryonic antigen affects the quality and amplitude of DNA vaccine-induced antibody responses in mice following intradermal delivery of DNA by a needle-free jet injection device (Biojector. CEA was expressed either in a membrane-bound form (wild-type CEA or in two truncated forms (CEA6 and CEA66 with cytoplasmic localization, where CEA66 was fused to a promiscuous T-helper epitope from tetanus toxin. Repeated intradermal immunization of BALB/c mice with DNA encoding wild-type CEA produced high antibody titers of a mixed IgG1/IgG2a ratio. In contrast, utilizing the DNA construct that resulted in intracellular targeting of CEA led to a reduced capacity to induce CEA-specific antibodies, but instead induced a Th1-biased immune response.

  2. Murine neonates develop vigorous in vivo cytotoxic and Th1/Th2 responses upon exposure to low doses of NIMA-like alloantigens.

    Science.gov (United States)

    Opiela, Shannon J; Levy, Robert B; Adkins, Becky

    2008-08-15

    Early life exposure to noninherited maternal antigens (NIMAs) may occur via transplacental transfer and/or breast milk. There are indications that early life exposure to NIMAs may lead to lifelong tolerance. However, there is mounting evidence that exposure to NIMAs may also lead to immunologic priming. Understanding how these different responses arise could be critical in transplantation with donor cells expressing NIMAs. We recently reported that murine neonates that received a transplant of low doses of NIMA-like alloantigens develop vigorous memory cytotoxic responses, as assessed by in vitro assays. Here, we demonstrate that robust allospecific cytotoxicity is also manifest in vivo. Importantly, at low doses, NIMA-expressing cells induced the development of in vivo cytotoxicity during the neonatal period. NIMA-exposed neonates also developed vigorous primary and memory allospecific Th1/Th2 responses that exceeded the responses of adults. Overall, we conclude that exposure to low doses of NIMA-like alloantigens induces robust in vivo cytotoxic and Th1/Th2 responses in neonates. These findings suggest that early exposure to low levels of NIMA may lead to long-term immunologic priming of all arms of T-cell adaptive immunity, rather than tolerance.

  3. Immunization of Mice by BCG Formulated HCV Core Protein Elicited Higher Th1-Oriented Responses Compared to Pluronic-F127 Copolymer

    Science.gov (United States)

    Yazdanian, Maryam; Memarnejadian, Arash; Mahdavi, Mehdi; Sadat, Seyed Mehdi; Motevali, Fatemeh; Vahabpour, Rouhollah; Khanahmad, Hossein; Siadat, Seyed Davar; Aghasadeghi, Mohammad Reza; Roohvand, Farzin

    2013-01-01

    Background A supreme vaccine for Hepatitis C virus (HCV) infection should elicit strong Th1-oriented cellular responses. In the absence of a Th1-specific adjuvant, immunizations by protein antigens generally induce Th2-type and weak cellular responses. Objectives To evaluate the adjuvant effect of BCG in comparison with nonionic copolymer-Pluronic F127 (F127) as a classic adjuvant in the formulation of HCV core protein (HCVcp) as a candidate vaccine for induction of Th1 immune responses. Materials and Methods Expression of N-terminally His-Tagged HCVcp (1-122) by pIVEX2.4a-core vector harboring the corresponding gene under the control of arabinose-inducible (araBAD) promoter was achieved in BL21-AI strain of E.coli and purified through application of nitrilotriacetic acid (Ni-NTA) chromatography. Mice were immunized subcutaneously (s.c.) in base of the tail with 100 μl of immunogen (F127+HCVcp or BCG+HCVcp; 5 μgHCVcp/mouse/dose) or control formulations (PBS, BCG, F127) at weeks 0, 3, 6. Total and subtypes of IgG, as well as cellular immune responses (Proliferation, In vivo CTL and IFN-γ/IL-4 ELISpot assays against a strong and dominant H2-d restricted, CD8+-epitopic peptide, core 39-48; RRGPRLGVRA of HCVcp) were compared in each group of immunized animals. Results Expression and purification of core protein around the expected size (21 kDa) was confirmed by Western blotting. The HCVcp + BCG vaccinated mice showed significantly higher lymphocyte proliferation and IFN-γ production but lower levels of cell lysis (45% versus 62% in CTL assay) than the HCVcp+F127 immunized animals. “Besides, total anti-core IgG and IgG1 levels were significantly higher in HCVcp + F127 immunized mice as compared to HCVcp + BCG vaccinated animals, indicating relatively higher efficacy of F127 for the stimulation of humoral and Th2-oriented immune responses”. Conclusions Results showed that HCVcp + BCG induced a moderate CTL and mixed Th1/Th2 immune responses with higher levels of

  4. Maintenance of Th1 hepatitis C virus (HCV)-specific responses in individuals with acute HCV who achieve sustained virological clearance after treatment.

    Science.gov (United States)

    Flynn, Jacqueline K; Dore, Gregory J; Hellard, Margaret; Yeung, Barbara; Rawlinson, William D; White, Peter A; Kaldor, John M; Lloyd, Andrew R; Ffrench, Rosemary A

    2013-11-01

    T-cell responses against hepatitis C are believed to be critical in achieving both natural and treatment-induced clearance. However, rapid clearance of antigen with early treatment of primary infection may result in reduced or poorly sustained cellular immunity. This study longitudinally examined Th1 and Th2 hepatitis C virus (HCV)-specific cytokine production and T-cell effector function from subjects enrolled in the Australian Trial in Acute Hepatitis C comparing three groups: treatment-induced clearance (sustained virological response [SVR]), treatment non-response, and untreated spontaneous clearance. HCV-specific T-cell responses were characterized by HCV peptide ELISpot, in vitro cytokine production, and T-cell flow cytometry assays. Treated subjects with a sustained virological response (SVR) displayed a better maintenance of HCV-specific Th1 responses compared to treatment non-responders (higher interferon [IFN]-γ and interleukin (IL)-2 magnitude at week 24, broader IFN-γ responses at weeks 24 and 48, P < 0.05) and significantly increased IFN-γ responses between screening and week 48 (magnitude P = 0.026, breadth P = 0.009). Treatment-induced viral clearance was also associated with a trend toward decreased IL-10 responses (screening to week 48, P = 0.070), higher expression of CD45RO (P = 0.042) and CD38 (P = 0.088) on CD4+ T cells, and higher IFN-γR expression (CD56+ IFN-γR+ P = 0.033) compared to treatment non-responders. Untreated subjects with viral clearance also displayed high magnitude and broad HCV-specific IFN-γ and IL-2 responses early in infection; however, IFN-γ responses were not as well maintained compared to treated subjects with a SVR (week 48 magnitude, breadth P = 0.064). Treatment-induced viral clearance of recent HCV infection is associated with maintenance of HCV-specific Th1 responses. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  5. Th1-type immune response to a Coccidioides immitis antigen delivered by an attenuated strain of the non-invasive enteropathogen Vibrio cholerae.

    Science.gov (United States)

    Silva, Anisia J; Benitez, Jorge A

    2005-03-01

    The antigen-2 or proline rich antigen (Ag2/PRA) from Coccidioides immitis, known to protect mice against experimental Coccidioidomycosis, was expressed in the genetically attenuated cholera vaccine candidate Vibrio cholerae 638 and its thymine auxotrophic derivative 638T. Intranasal immunization of mice with strains producing Ag2/PRA induced serum vibriocidal antibody and Ag2/PRA-specific total IgG responses in outbred Swiss Webster and inbred BALB/c mice. Analysis of IgG subclasses showed a predominance of IgG2a subclass antibodies. Lymphocytes from immunized mice stimulated with pure Ag2/PRA showed a significant proliferative response with production of interferon-gamma. Positive selection for plasmid maintenance in vivo did not enhance immune response to Ag2/PRA. These results demonstrate that genetically attenuated strains of the non-invasive pathogen V. cholerae can be used to express and deliver foreign antigens to stimulate a Th1 type of immune response.

  6. ESAT-6- and CFP-10-specific Th1, Th22 and Th17 cells in tuberculous pleurisy may contribute to the local immune response against Mycobacterium tuberculosis infection.

    Science.gov (United States)

    Qiao, D; Yang, B Y; Li, L; Ma, J J; Zhang, X L; Lao, S H; Wu, C Y

    2011-04-01

    Th1 cell-mediated adaptive immune response is very important but may not be sufficient to control Mycobacterium tuberculosis (M. tuberculosis) infection. The roles of the various T cell subsets and cytokines in the inflammatory processes are not clearly elucidated. We investigated whether Th1, Th22 and Th17 cells mediated cellular immunity at the local site of M. tuberculosis infection in patients with tuberculous pleurisy (TBP). The results showed that the cytokines IFN-γ and IL-22 but not IL-17 were elevated in tubercular pleural fluid. Following stimulation with immune-dominant peptides of early secreted antigenic target-6 (ESAT-6), culture filtrate protein-10 (CFP-10) or Bacille Calmette-Guerin, pleural fluid mononuclear cells expressed high levels of cytokines IFN-γ, IL-22 and IL-17 as revealed by mRNA and protein measurements. In addition, we showed that cytokines IFN-γ, IL-22 and IL-17 were produced in M. tuberculosis-specific immune response by distinct subsets of CD4+ T cells with the phenotype of CD45RA-CD62L-CCR7+CD27+ . Our results demonstrated for the first time that ESAT-6- and CFP-10-specific Th1, Th22 and Th17 cells existed in the patients with TBP and might play an essential role against M. tuberculosis infection. The findings of this study raised the possibility of unravelling the critical targets for therapeutic intervention in chronic inflammatory diseases such as TBP. © 2011 The Authors. Scandinavian Journal of Immunology © 2011 Blackwell Publishing Ltd.

  7. IFN-α Boosting of Mycobacterium bovis Bacillus Calmette Güerin-Vaccine Promoted Th1 Type Cellular Response and Protection against M. tuberculosis Infection

    Science.gov (United States)

    Rivas-Santiago, C. E.

    2017-01-01

    The role of type I IFNs in the pathogenesis and control of mycobacterial infection is still controversial. It has been reported that type I IFNs exacerbated M. tuberculosis infection through hampering Th1 type cellular immune response. However, under certain conditions they can act as natural immune adjuvants for commercial vaccines. At this point, we have reported recently that successive IFN-alpha boosting of Mycobacterium bovis Bacillus Calmette Güerin (BCG) vaccinated mice protected adult mice from intradermal M. lepraemurium infection and a difference in iNOS was observed. In the present work, we have found that intramuscular IFN-α boosting of Mycobacterium bovis Bacillus Calmette Güerin (BCG) vaccine, either in vitro (human cell line or macrophages derived from PBMC) or in vivo (aerosol mouse model of MTb infection), promoted mostly the development of specific anti-antimycobacterial Th1 type cytokines (IFN-γ; IL-12, TNF-alpha, and IL-17; IL1β) while bacterial load reduction (0.9 logs versus PBS or BCG vaccine) was observed. These findings indicate that, under the experimental settings reported here, interferon alpha can drive or affect the TH cellular immune response in favour of BCG-inducing immunity against M. tuberculosis infection. PMID:29090221

  8. Interleukin-12 Induces a Th1-Like Response to Burkholderia mallei and Limited Protection in BALB/c Mice

    Science.gov (United States)

    2006-01-01

    dependent on the concentration of IL-12. Mahon et al. [21] demonstrated that IL-12 increased the efficacy of a Bordetella pertussis acellular vaccine...Interleukin-12 is pro- duced by macrophages in response to live or killed Bordetella per- tussis and enhances the efficacy of an acellular pertussis

  9. Long-Lasting Effects of BCG Vaccination on Both Heterologous Th1/Th17 Responses and Innate Trained Immunity

    NARCIS (Netherlands)

    Kleinnijenhuis, J.; Quintin, J.; Preijers, F.W.M.B.; Benn, C.S.; Joosten, L.A.B.; Jacobs, C.W.; Loenhout, J. van; Xavier, R.J.; Aaby, P.; Meer, J.W.M. van der; Crevel, R. van; Netea, M.G.

    2014-01-01

    We have recently shown that BCG (Bacillus Calmette-Guerin) vaccination in healthy volunteers induces epigenetic reprogramming of monocytes, leading to increased cytokine production in response to nonrelated pathogens for up to 3 months after vaccination. This phenomenon was named 'trained immunity'.

  10. Lithocholic acid controls adaptive immune responses by inhibition of Th1 activation through the Vitamin D receptor

    NARCIS (Netherlands)

    Pols, Thijs W. H.; Puchner, Teresa; Korkmaz, H. Inci; Vos, Mariska; Soeters, Maarten R.; de Vries, Carlie J. M.

    2017-01-01

    Bile acids are established signaling molecules next to their role in the intestinal emulsification and uptake of lipids. We here aimed to identify a potential interaction between bile acids and CD4+ Th cells, which are central in adaptive immune responses. We screened distinct bile acid species for

  11. Pre-existing adenovirus immunity modifies a complex mixed Th1 and Th2 cytokine response to an Ad5/HIV-1 vaccine candidate in humans.

    Directory of Open Access Journals (Sweden)

    Samuel O Pine

    2011-04-01

    Full Text Available The results of the recent Step Study highlight a need to clarify the effects of pre-existing natural immunity to a vaccine vector on vaccine-induced T-cell responses. To investigate this interaction, we examined the relationship between pre-existing Ad5 immunity and T-cell cytokine response profiles in healthy, HIV-uninfected recipients of MRKAd5 HIV-1 gag vaccine (HVTN 050, ClinicalTrials.gov #NCT00849732. Participants were grouped by baseline Ad5 neutralizing antibody titer as either Ad5-seronegative (titer ≤18; n = 36 or Ad5-seropositive (titer >200; n = 34. Samples from vaccine recipients were analyzed for immune responses to either HIV-1 Gag peptide pools or Ad5 empty vector using an ex vivo assay that measures thirty cytokines in the absence of long-term culture. The overall profiles of cytokine responses to Gag and Ad5 had similar combinations of induced Th1- and Th2-type cytokines, including IFN-γ, IL-2, TNF-α, IP-10, IL-13, and IL-10, although the Ad5-specific responses were uniformly higher than the Gag-specific responses (p<0.0001 for 9 out of 11 significantly expressed analytes. At the peak response time point, PBMC from Ad5-seronegative vaccinees secreted significantly more IP-10 in response to Gag (p = 0.008, and significantly more IP-10 (p = 0.0009, IL-2 (p = 0.006 and IL-10 (p = 0.05 in response to Ad5 empty vector than PBMC from Ad5-seropositive vaccinees. Additionally, similar responses to the Ad5 vector prior to vaccination were observed in almost all subjects, regardless of Ad5 neutralizing antibody status, and the levels of secreted IFN-γ, IL-10, IL-1Ra and GM-CSF were blunted following vaccination. The cytokine response profile of Gag-specific T cells mirrored the Ad5-specific response present in all subjects before vaccination, and included a number of Th1- and Th2-associated cytokines not routinely assessed in current vaccine trials, such as IP-10, IL-10, IL-13, and GM-CSF. Together, these

  12. [EFFECT OF 4-METHYLPYRAZOLE ON IMMUNE RESPONSE, FUNCTION OF Th1 AND Th2 LYMPHOCYTES, AND CYTOKINE CONCENTRATION IN RAT BLOOD AFTER ACUTE METHANOL POISONING].

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    Zabrodskii, P F; Maslyakov, V V; Gromov, M S

    2016-01-01

    It was established in experiments on noninbred albino rats that the acute intoxication with methanol (1.0 LD50) decreased cellular and humoral immune responses, Th2-lymphocyte activity (to a greater extent as compared to the function of Th1 cells), reduced the blood concentration of immunoregulatory (IFN-g, IL-2, IL-4) and proinflammatory (TNF, IL-1b, IL-6) cytokines on the average by 36.5% (p Methanol antidote 4-methylpyrazole (non-competitive inhibitor of alcohol dehydrogenase) administered upon acute intoxication with methanol at a dose of 1.0 DL50 partially reduces the intoxication-induced suppression of humoral and cellular immune response, activity of T-helper cells, and production of IL-4 and restores blood levels of TNF, IL-1b, IFN-γ, IL-4, IL-2, IL-6 to the control values.

  13. A De-O-acylated Lipooligosaccharide-Based Adjuvant System Promotes Antibody and Th1-Type Immune Responses to H1N1 Pandemic Influenza Vaccine in Mice

    Directory of Open Access Journals (Sweden)

    Ji In Ryu

    2016-01-01

    Full Text Available Vaccine adjuvants are agents that are used to promote immune responses to vaccine antigens and thereby to enhance the protective efficacy of the vaccines. In this study, we investigated the adjuvant activity of CIA06, an adjuvant system that is composed of a toll-like receptor 4 agonist de-O-acylated lipooligosaccharide (dLOS and aluminum hydroxide, on the H1N1 pandemic influenza vaccine Greenflu-S® in mice. CIA06 significantly enhanced influenza-specific serum IgG, hemagglutination-inhibition, and virus-neutralizing antibody titers, which eliminated vaccine dose-dependency in the antibody response. Mice immunized with the CIA06-adjuvanted Greenflu-S showed Th1-type-predominant cytokine profiles, and both CD4+ and CD8+ T cell responses were induced. Immunization of mice with the CIA06-adjuvanted vaccine reduced the mortality and morbidity of mice upon lethal challenges with influenza virus, and no excessive inflammatory responses were observed in the lung tissues of the immunized mice after viral infection. These data suggest that the dLOS-based adjuvant system CIA06 can be used to promote the immune responses to influenza vaccine or to spare antigen dose without causing harmful inflammatory responses.

  14. A novel recombinant Leishmania donovani p45, a partial coding region of methionine aminopeptidase, generates protective immunity by inducing a Th1 stimulatory response against experimental visceral leishmaniasis.

    Science.gov (United States)

    Gupta, Reema; Kushawaha, Pramod K; Tripathi, Chandra Dev Pati; Sundar, Shyam; Dube, Anuradha

    2012-05-01

    The development of a vaccine against visceral leishmaniasis (VL) conferring long-lasting immunity remains a challenge. Identification and proteomic characterization of parasite proteins led to the detection of p45, a member of the methionine aminopeptidase family. To our knowledge the present study is the first known report that describes the molecular and immunological characterization of p45. Recombinant Leishmania donovani p45 (rLdp45) induced cellular responses in cured hamsters and generated Th1-type cytokines from peripheral blood mononuclear cells of cured/endemic VL patients. Immunization with rLdp45 exerted considerable prophylactic efficacy (∼85%) supported by an increase in mRNA expression of iNOS, IFN-γ, TNF-α and IL-12 and decrease in TGF-β and IL-4, indicating its potential as a vaccine candidate against VL. Copyright © 2012. Published by Elsevier Ltd.

  15. Elongation factor-2, a Th1 stimulatory protein of Leishmania donovani, generates strong IFN-γ and IL-12 response in cured Leishmania-infected patients/hamsters and protects hamsters against Leishmania challenge.

    Science.gov (United States)

    Kushawaha, Pramod K; Gupta, Reema; Sundar, Shyam; Sahasrabuddhe, Amogh A; Dube, Anuradha

    2011-12-15

    In visceral leishmaniasis, Th1 types of immune responses correlate with recovery from and resistance to disease, and resolution of infection results in lifelong immunity against the disease. Leishmanial Ags that elicit proliferative and cytokine responses in PBMCs from cured/exposed/Leishmania patients have been characterized through proteomic approaches, and elongation factor-2 is identified as one of the potent immunostimulatory proteins. In this study, we report the cloning and expression of Leishmania donovani elongation factor-2 protein (LelF-2) and its immunogenicity in PBMCs of cured/exposed Leishmania-infected patients and hamsters (Mesocricetus auratus). Leishmania-infected cured/exposed patients and hamsters exhibited significantly higher proliferative responses to recombinant Lelf-2 (rLelF-2) than those with L. donovani-infected hosts. The soluble L. donovani Ag stimulated PBMCs of cured/exposed and Leishmania patients to produce a mixed Thl/Th2-type cytokine profile, whereas rLelF-2 stimulated the production of IFN-γ, IL-12, and TNF-α but not IL-4 or IL-10. Further, rLelF-2 downregulated LPS-induced IL-10 as well as soluble L. donovani Ag-induced IL-4 production by Leishmania patient PBMCs. The immunogenicity of rLelF-2 was also checked in hamsters in which rLelF-2 generates strong IL-12- and IFN-γ-mediated Th1 immune response. This was further supported by a remarkable increase in IgG2 Ab level. We further demonstrated that rLelF-2 was able to provide considerable protection (∼65%) to hamsters against L. donovani challenge. The efficacy was supported by the increased inducible NO synthase mRNA transcript and Th1-type cytokines IFN-γ, IL-12, and TNF-α and downregulation of IL-4, IL-10, and TGF-β. Hence, it is inferred that rLelF-2 elicits a Th1 type of immune response exclusively and confers considerable protection against experimental visceral leishmaniasis.

  16. Evaluation of Th1-like, Th2-like and immunomodulatory cytokine mRNA expression in the skin of dogs with immunomodulatory-responsive lymphocytic-plasmacytic pododermatitis.

    Science.gov (United States)

    Breathnach, Rory M; Fanning, Shay; Mulcahy, Grace; Bassett, Hugh F; Jones, Boyd R; Daly, Paul

    2006-10-01

    The term immunomodulatory-responsive lymphocytic-plasmacytic pododermatitis (ImR-LPP) has previously been proposed to denote a subpopulation of dogs with idiopathic pododermatitis. The objective of this study was to quantify the expression of mRNA encoding Th(1)-like [interferon (IFN)-gamma, interleukin (IL)-2 and IL-12], Th(2)-like [IL-4 and IL-6] and immunomodulatory cytokines [IL-10 and transforming growth factor (TGF)-beta] in lesional ImR-LPP, nonlesional ImR-LPP and healthy control pedal skin. Gene transcripts were quantified using TaqMan real-time reverse transcriptase-polymerase chain reaction assays. The skin of dogs with ImR-LPP had significant overexpression of IL-6 mRNA (P < 0.05) and significant underexpression of IL-12 mRNA (P < 0.01) compared to healthy controls. In addition, lesional ImR-LPP skin had significantly higher levels of IL-10 transcripts compared to healthy control pedal skin (P < 0.05). Although not attaining significance (P = 0.07), a trend towards reduced TGF-beta mRNA expression in lesional ImR-LPP skin was also evident. There were no significant differences in the levels of IFN-gamma or IL-2 mRNA transcripts among the three skin sample sources. IL-4 mRNA was detected in only one lesional sample. These results suggest that the pathogenesis of ImR-LPP may be associated with a T-cell-mediated inflammatory response characterized by impaired Th(1)-like, but enhanced Th(2)-like cytokine expression.

  17. Extracellular vesicles, especially derived from Gram-negative bacteria, in indoor dust induce neutrophilic pulmonary inflammation associated with both Th1 and Th17 cell responses.

    Science.gov (United States)

    Kim, Y-S; Choi, E-J; Lee, W-H; Choi, S-J; Roh, T-Y; Park, J; Jee, Y-K; Zhu, Z; Koh, Y-Y; Gho, Y S; Kim, Y-K

    2013-04-01

    Many bacterial components in indoor dust can evoke inflammatory pulmonary diseases. Bacteria secrete nanometre-sized vesicles into the extracellular milieu, but it remains to be determined whether bacteria-derived extracellular vesicles in indoor dust are pathophysiologically related to inflammatory pulmonary diseases. To evaluate whether extracellular vesicles (EV) in indoor air are related to the pathogenesis of pulmonary inflammation and/or asthma. Indoor dust was collected from a bed mattress in an apartment. EV were prepared by sequential ultrafiltration and ultracentrifugation. Innate and adaptive immune responses were evaluated after airway exposure of EV. Repeated intranasal application of indoor-dust-induced neutrophilic pulmonary inflammation accompanied by lung infiltration of both Th1 and Th17 cells. EV 50-200 nm in diameter were present (102.5 μg protein concentration/g dust) in indoor dust. These vesicles were internalized by airway epithelial cells and alveolar macrophages, and this process was blocked by treatment of polymyxin B (an antagonist of lipopolysaccharide, an outer-membrane component of Gram-negative bacteria). Intranasal application of 0.1 or 1 μg of these vesicles for 4 weeks elicited neutrophilic pulmonary inflammation. This phenotype was accompanied by lung infiltration of both Th1 and Th17 cells, which were reversed by treatment of polymyxin B. Serum dust EV-reactive IgG1 levels were significantly higher in atopic children with asthma than in atopic healthy children and those with rhinitis or dermatitis. Indoor dust EV, especially derived from Gram-negative bacteria, is a possible causative agent of neutrophilic airway diseases. © 2013 Blackwell Publishing Ltd.

  18. Genetically Modified Live Attenuated Leishmania donovani Parasites Induce Innate Immunity through Classical Activation of Macrophages That Direct the Th1 Response in Mice

    Science.gov (United States)

    Bhattacharya, Parna; Dey, Ranadhir; Dagur, Pradeep K.; Kruhlak, Michael; Ismail, Nevien; Debrabant, Alain; Joshi, Amritanshu B.; Akue, Adovi; Kukuruga, Mark; Takeda, Kazuyo; Selvapandiyan, Angamuthu; McCoy, John Philip

    2015-01-01

    Visceral leishmaniasis (VL) causes significant mortality and there is no effective vaccine. Previously, we have shown that genetically modified Leishmania donovani parasites, here described as live attenuated parasites, induce a host protective adaptive immune response in various animal models. In this study, we demonstrate an innate immune response upon infection with live attenuated parasites in macrophages from BALB/c mice both in vitro and in vivo. In vitro infection of macrophages with live attenuated parasites (compared to that with wild-type [WT] L. donovani parasites) induced significantly higher production of proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin-12 [IL-12], gamma interferon [IFN-γ], and IL-6), chemokines (monocyte chemoattractant protein 1/CCL-2, macrophage inflammatory protein 1α/CCL-3, and IP-10), reactive oxygen species (ROS), and nitric oxide, while concomitantly reducing anti-inflammatory cytokine IL-10 and arginase-1 activities, suggesting a dominant classically activated/M1 macrophage response. The classically activated response in turn helps in presenting antigen to T cells, as observed with robust CD4+ T cell activation in vitro. Similarly, parasitized splenic macrophages from live attenuated parasite-infected mice also demonstrated induction of an M1 macrophage phenotype, indicated by upregulation of IL-1β, TNF-α, IL-12, and inducible nitric oxide synthase 2 and downregulation of genes associated with the M2 phenotype, i.e., the IL-10, YM1, Arg-1, and MRC-1 genes, compared to WT L. donovani-infected mice. Furthermore, an ex vivo antigen presentation assay showed macrophages from live attenuated parasite-infected mice induced higher IFN-γ and IL-2 but significantly less IL-10 production by ovalbumin-specific CD4+ T cells, resulting in proliferation of Th1 cells. These data suggest that infection with live attenuated parasites promotes a state of classical activation (M1 dominant) in macrophages that

  19. Genetically Modified Live Attenuated Leishmania donovani Parasites Induce Innate Immunity through Classical Activation of Macrophages That Direct the Th1 Response in Mice.

    Science.gov (United States)

    Bhattacharya, Parna; Dey, Ranadhir; Dagur, Pradeep K; Kruhlak, Michael; Ismail, Nevien; Debrabant, Alain; Joshi, Amritanshu B; Akue, Adovi; Kukuruga, Mark; Takeda, Kazuyo; Selvapandiyan, Angamuthu; McCoy, John Philip; Nakhasi, Hira L

    2015-10-01

    Visceral leishmaniasis (VL) causes significant mortality and there is no effective vaccine. Previously, we have shown that genetically modified Leishmania donovani parasites, here described as live attenuated parasites, induce a host protective adaptive immune response in various animal models. In this study, we demonstrate an innate immune response upon infection with live attenuated parasites in macrophages from BALB/c mice both in vitro and in vivo. In vitro infection of macrophages with live attenuated parasites (compared to that with wild-type [WT] L. donovani parasites) induced significantly higher production of proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin-12 [IL-12], gamma interferon [IFN-γ], and IL-6), chemokines (monocyte chemoattractant protein 1/CCL-2, macrophage inflammatory protein 1α/CCL-3, and IP-10), reactive oxygen species (ROS), and nitric oxide, while concomitantly reducing anti-inflammatory cytokine IL-10 and arginase-1 activities, suggesting a dominant classically activated/M1 macrophage response. The classically activated response in turn helps in presenting antigen to T cells, as observed with robust CD4(+) T cell activation in vitro. Similarly, parasitized splenic macrophages from live attenuated parasite-infected mice also demonstrated induction of an M1 macrophage phenotype, indicated by upregulation of IL-1β, TNF-α, IL-12, and inducible nitric oxide synthase 2 and downregulation of genes associated with the M2 phenotype, i.e., the IL-10, YM1, Arg-1, and MRC-1 genes, compared to WT L. donovani-infected mice. Furthermore, an ex vivo antigen presentation assay showed macrophages from live attenuated parasite-infected mice induced higher IFN-γ and IL-2 but significantly less IL-10 production by ovalbumin-specific CD4(+) T cells, resulting in proliferation of Th1 cells. These data suggest that infection with live attenuated parasites promotes a state of classical activation (M1 dominant) in macrophages that

  20. SjCRT, a recombinant Schistosoma japonicum calreticulin, induces maturation of dendritic cells and a Th1-polarized immune response in mice

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    Lizhen Ma

    2017-11-01

    Full Text Available Abstract Background It is well known that immunization of radiation-attenuated (RA schistosoma cercariae or schistosomula can induce high levels of protective immunity against schistosoma cercariae reinfection in many animals. Many studies have shown that the Th1 cellular immune response is crucial for the protective effect elicited by RA schistosomula. However, the molecular mechanism of this strong protective immunity remains unclear. Methods The expression profiles of Schistosoma japonicum calreticulin (SjCRT in RA and normal schistosoma-derived cells were investigated by flow cytometry. The effect of recombinant SjCRT (rSjCRT on mouse dendritic cells (DCs was determined by FACS, ELISA and RT-PCR analysis. We also analyzed the effects of SjCRT on the activation of spleen cells from mice immunized with rSjCRT by detecting lymphocyte proliferation and the cytokine profiles of splenocytes. Results We found that the expression level of SjCRT in the cells from RA larvae was significantly higher than that in cells from normal schistosomula at early stages of development (day 4. The results of effect of rSjCRT on mouse DCs showed that rSjCRT could induce phenotypic and functional maturation of DCs, and SjCRT bound to the surface of DCs through the CD91 receptor and could be engulfed by DCs. The results of activation of splenocytes from mice immunized with rSjCRT also demonstrate that rSjCRT can effectively stimulate the proliferative response of splenic lymphocytes, elicit splenocytes from immunized mice to secrete high levels of IFN-γ, TNF-α and IL-4, and activate CD4+ T cells to produce high levels of IFN-γ. Conclusion SjCRT is one of the immunostimulatory molecules released from RA schistosomula cells, might play a crucial role in conferring a Th1-polarized immune response induced by RA cercariae/schistosomula in mice, and is a candidate molecule responsible for the high levels of protective immunity induced by RA schistosomula.

  1. A Built-In CpG Adjuvant in RSV F Protein DNA Vaccine Drives a Th1 Polarized and Enhanced Protective Immune Response

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    Yao Ma

    2018-01-01

    Full Text Available Human respiratory syncytial virus (RSV is the most significant cause of acute lower respiratory infection in children. However, there is no licensed vaccine available. Here, we investigated the effect of five or 20 copies of C-Class of CpG ODN (CpG-C motif incorporated into a plasmid DNA vaccine encoding RSV fusion (F glycoprotein on the vaccine-induced immune response. The addition of CpG-C motif enhanced serum binding and virus-neutralizing antibody responses in BALB/c mice immunized with the DNA vaccines. Moreover, mice vaccinated with CpG-modified vaccines, especially with the higher 20 copies, resulted in an enhanced shift toward a Th1-biased antibody and T-cell response, a decrease in pulmonary pathology and virus replication, and a decrease in weight loss after RSV challenge. This study suggests that CpG-C motif, cloned into the backbone of DNA vaccine encoding RSV F glycoprotein, functions as a built-in adjuvant capable of improving the efficacy of DNA vaccine against RSV infection.

  2. Toll-like receptor 9 is required for full host resistance to Mycobacterium avium infection but plays no role in induction of Th1 responses.

    Science.gov (United States)

    Carvalho, Natália B; Oliveira, Fernanda S; Durães, Fernanda V; de Almeida, Leonardo A; Flórido, Manuela; Prata, Luana O; Caliari, Marcelo V; Appelberg, Rui; Oliveira, Sérgio C

    2011-04-01

    To investigate the role of Toll-like receptor 9 (TLR9) in innate immunity to Mycobacterium avium, TLR9, TLR2, and MyD88 knockout (KO) mice were infected with this bacterium. Bacterial burdens were higher in the spleens, livers, and lungs of infected TLR9 KO mice than in those of C57BL/6 mice, indicating that TLR9 is required for efficient control of M. avium infection. However, TLR9 KO or TLR2 KO spleen cells displayed normal M. avium-induced tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) responses. This finding was confirmed by determining the number of splenic CD4(+) T cells producing IFN-γ by flow cytometry. Furthermore, TLR2 and MyD88, but not TLR9, played a major role in interleukin-12 and TNF-α production by M. avium-infected macrophages and dendritic cells (DCs). We also found that major histocompatibility complex class II molecule expression on DCs is regulated by TLR2 and MyD88 signaling but not by TLR9. Finally, lack of TLR9, TLR2, or MyD88 reduced the numbers of macrophages, epithelioid cells, and lymphocytes in M. avium-induced granulomas but only MyD88 deficiency affected the number of liver granulomas. In summary, our data demonstrated that the involvement of TLR9 in the control of M. avium infection is not related to the induction of Th1 responses.

  3. Brucella abortus strain RB51 as a vector for heterologous protein expression and induction of specific Th1 type immune responses.

    Science.gov (United States)

    Vemulapalli, R; He, Y; Boyle, S M; Sriranganathan, N; Schurig, G G

    2000-06-01

    Brucella abortus strain RB51 is a stable, rough, attenuated mutant widely used as a live vaccine for bovine brucellosis. Our ultimate goal is to develop strain RB51 as a preferential vector for the delivery of protective antigens of other intracellular pathogens to which the induction of a strong Th1 type of immune response is needed for effective protection. As a first step in that direction, we studied the expression of a foreign reporter protein, beta-galactosidase of Escherichia coli, and the 65-kDa heat shock protein (HSP65) of Mycobacterium bovis in strain RB51. We cloned the promoter sequences of Brucella sodC and groE genes in pBBR1MCS to generate plasmids pBBSODpro and pBBgroE, respectively. The genes for beta-galactosidase (lacZ) and HSP65 were cloned in these plasmids and used to transform strain RB51. An enzyme assay in the recombinant RB51 strains indicated that the level of beta-galactosidase expression is higher under the groE promoter than under the sodC promoter. In strain RB51 containing pBBgroE/lacZ, but not pBBSODpro/lacZ, increased levels of beta-galactosidase expression were observed after subjecting the bacteria to heat shock or following internalization into macrophage-like J774A.1 cells. Mice vaccinated with either of the beta-galactosidase-expressing recombinant RB51 strains developed specific antibodies of predominantly the immunoglobulin G2a (IgG2a) isotype, and in vitro stimulation of their splenocytes with beta-galactosidase induced the secretion of gamma interferon (IFN-gamma), but not interleukin-4 (IL-4). A Th1 type of immune response to HSP65, as indicated by the presence of specific serum IgG2a, but not IgG1, antibodies, and IFN-gamma, but not IL-4, secretion by the specific-antigen-stimulated splenocytes, was also detected in mice vaccinated with strain RB51 containing pBBgroE/hsp65. Studies with mice indicated that expression of beta-galactosidase or HSP65 did not alter either the attenuation characteristics of strain RB51 or

  4. Immunization of Mice with a Live Transconjugant Shigella Hybrid Strain Induced Th1 and Th17 Cell-Mediated Immune Responses and Confirmed Passive Protection Against Heterologous Shigellae.

    Science.gov (United States)

    Nag, D; Koley, H; Sinha, R; Mukherjee, P; Sarkar, C; Withey, J H; Gachhui, R

    2016-02-01

    An avirulent, live transconjugant Shigella hybrid (LTSHΔstx) strain was constructed in our earlier study by introducing a plasmid vector, pPR1347, into a Shiga toxin gene deleted Shigella dysenteriae 1. Three successive oral administrations of LTSHΔstx to female adult mice produced comprehensive passive heterologous protection in their offspring against challenge with wild-type shigellae. Production of NO and different cytokines such asIL-12p70, IL-1β and IL-23 in peritoneal mice macrophages indicated that LTSHΔstx induced innate and adaptive immunity in mice. Furthermore, production of IFN-γ, IL-10 and IL-17 in LTSH-primed splenic CD4+ T cell suggested that LTSHΔstx may induce Th1 and Th17 cell-mediated immune responses. Exponential increase of the serum IgG and IgA titre against whole shigellae was observed in immunized adult mice during and after the immunization with the highest peak on day 35. Antigen-specific sIgA was also determined from intestinal lavage of immunized mice. The stomach extracts of neonates from immunized mice, mainly containing mother's milk, contained significant levels of anti-LTSHΔstx immunoglobulin. These studies suggest that the LTSHΔstx could be a new live oral vaccine candidate against shigellosis in the near future. © 2015 The Foundation for the Scandinavian Journal of Immunology.

  5. Dichotomy of the human T cell response to Leishmania antigens. II. Absent or Th2-like response to gp63 and Th1-like response to lipophosphoglycan-associated protein in cells from cured visceral leishmaniasis patients

    DEFF Research Database (Denmark)

    Kurtzhals, J A; Hey, A S; Jardim, A

    1994-01-01

    The T cell response to different Leishmania donovani antigens was investigated using peripheral blood mononuclear cells (PBMC) from Kenyans cured of visceral leishmaniasis and non-exposed Danes. Crude promastigote and amastigote antigens both induced proliferation and interferon-gamma (IFN...... in five of 17 samples from cured patients. Four of the five responding cultures produced IL-4, i.e. the response to this antigen was of the Th2 type. Furthermore, sera from acutely ill visceral leishmaniasis patients contained high levels of IgG antibodies to gp63. The Th2-like response to gp63...... in patients cured of visceral leishmaniasis differs from the Th1-like response to the same antigen observed in patients cured of cutaneous leishmaniasis....

  6. Unlipidated Outer Membrane Protein Omp16 (U-Omp16) from Brucella spp. as Nasal Adjuvant Induces a Th1 Immune Response and Modulates the Th2 Allergic Response to Cow’s Milk Proteins

    Science.gov (United States)

    Ibañez, Andrés E.; Smaldini, Paola; Coria, Lorena M.; Delpino, María V.; Pacífico, Lucila G. G.; Oliveira, Sergio C.; Risso, Gabriela S.; Pasquevich, Karina A.; Fossati, Carlos Alberto; Giambartolomei, Guillermo H.; Docena, Guillermo H.; Cassataro, Juliana

    2013-01-01

    The discovery of novel mucosal adjuvants will help to develop new formulations to control infectious and allergic diseases. In this work we demonstrate that U-Omp16 from Brucella spp. delivered by the nasal route (i.n.) induced an inflammatory immune response in bronchoalveolar lavage (BAL) and lung tissues. Nasal co-administration of U-Omp16 with the model antigen (Ag) ovalbumin (OVA) increased the amount of Ag in lung tissues and induced OVA-specific systemic IgG and T helper (Th) 1 immune responses. The usefulness of U-Omp16 was also assessed in a mouse model of food allergy. U-Omp16 i.n. administration during sensitization ameliorated the hypersensitivity responses of sensitized mice upon oral exposure to Cow’s Milk Protein (CMP), decreased clinical signs, reduced anti-CMP IgE serum antibodies and modulated the Th2 response in favor of Th1 immunity. Thus, U-Omp16 could be used as a broad Th1 mucosal adjuvant for different Ag formulations. PMID:23861971

  7. Unlipidated outer membrane protein Omp16 (U-Omp16 from Brucella spp. as nasal adjuvant induces a Th1 immune response and modulates the Th2 allergic response to cow's milk proteins.

    Directory of Open Access Journals (Sweden)

    Andrés E Ibañez

    Full Text Available The discovery of novel mucosal adjuvants will help to develop new formulations to control infectious and allergic diseases. In this work we demonstrate that U-Omp16 from Brucella spp. delivered by the nasal route (i.n. induced an inflammatory immune response in bronchoalveolar lavage (BAL and lung tissues. Nasal co-administration of U-Omp16 with the model antigen (Ag ovalbumin (OVA increased the amount of Ag in lung tissues and induced OVA-specific systemic IgG and T helper (Th 1 immune responses. The usefulness of U-Omp16 was also assessed in a mouse model of food allergy. U-Omp16 i.n. administration during sensitization ameliorated the hypersensitivity responses of sensitized mice upon oral exposure to Cow's Milk Protein (CMP, decreased clinical signs, reduced anti-CMP IgE serum antibodies and modulated the Th2 response in favor of Th1 immunity. Thus, U-Omp16 could be used as a broad Th1 mucosal adjuvant for different Ag formulations.

  8. Schistosoma mansoni tegument protein Sm29 is able to induce a Th1-type of immune response and protection against parasite infection.

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    Fernanda C Cardoso

    Full Text Available BACKGROUND: Schistosomiasis continues to be a significant public health problem. This disease affects 200 million people worldwide and almost 800 million people are at risk of acquiring the infection. Although vaccine development against this disease has experienced more failures than successes, encouraging results have recently been obtained using membrane-spanning protein antigens from the tegument of Schistosoma mansoni. Our group recently identified Sm29, another antigen that is present at the adult worm tegument surface. In this study, we investigated murine cellular immune responses to recombinant (r Sm29 and tested this protein as a vaccine candidate. METHODS AND FINDINGS: We first show that Sm29 is located on the surface of adult worms and lung-stage schistosomula through confocal microscopy. Next, immunization of mice with rSm29 engendered 51%, 60% and 50% reduction in adult worm burdens, in intestinal eggs and in liver granuloma counts, respectively (p<0.05. Protective immunity in mice was associated with high titers of specific anti-Sm29 IgG1 and IgG2a and elevated production of IFN-gamma, TNF-alpha and IL-12, a typical Th1 response. Gene expression analysis of worms recovered from rSm29 vaccinated mice relative to worms from control mice revealed a significant (q<0.01 down-regulation of 495 genes and up-regulation of only 22 genes. Among down-regulated genes, many of them encode surface antigens and proteins associated with immune signals, suggesting that under immune attack schistosomes reduce the expression of critical surface proteins. CONCLUSION: This study demonstrates that Sm29 surface protein is a new vaccine candidate against schistosomiasis and suggests that Sm29 vaccination associated with other protective critical surface antigens is the next logical strategy for improving protection.

  9. Intratumoral delivery of IL-18 naked DNA induces T-cell activation and Th1 response in a mouse hepatic cancer model

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    Joh Jae-Won

    2007-05-01

    Full Text Available Abstract Background The novel cytokine, interleukin (IL-18, is a strong interferon-γ inducer and costimulatory factor in Th1 cell activation. IL-18 triggers IFN-γ production and enhances cytolytic activity in both T and NK cells. However, the exact mechanism of antitumor action of IL-18 remains to be clarified. To determine the effects of IL-18 plasmid DNA on hepatic cancer in mice, CT26 murine colon adenocarcinoma cells were established in mouse liver. Methods Plasmid vectors encoding IL-18 were transferred directly into the liver 7 days after tumor injection to restrict IL-18 expression within the tumor site. The IL-18 protein level was increased in the liver 4 days after plasmid injection, and a marked antitumoral effect was observed at day 7. Antitumor effects were evaluated by measuring tumor regression, immune cell population, and IFN-γ production. Results The IL-18 plasmid controlled the growth of hepatic tumors and proliferation of splenic immune cells. Moreover, treatment of CT26 tumors with the IL-18 plasmid significantly enhanced the population of the effector T and NK cells in the spleen and peripheral blood. In spleen, the population of CD4+CD62Low cells was augmented in response to IL-18 on day 7. These results are consistent with the increase in CD4+ T cells secreting IFN-γ, but not CD8+ T cells. The marked reduction of tumor growth in tumor-bearing mice was associated with the maintenance of IFN-γ production in spleen in response to IL-18. These antitumoral effects were maintained until 14 days after plasmid injection. Conclusion Our results suggest that direct plasmid DNA transfer of IL-18 with no accompanying reagents to augment transfection efficiency may be useful in tumor immunotherapy.

  10. Distinct Roles of Th17 and Th1 Cells in Inflammatory Responses Associated with the Presentation of Paucibacillary Leprosy and Leprosy Reactions.

    Science.gov (United States)

    Santos, M B; de Oliveira, D T; Cazzaniga, R A; Varjão, C S; Dos Santos, P L; Santos, M L B; Correia, C B; Faria, D R; Simon, M do V; Silva, J S; Dutra, W O; Reed, S G; Duthie, M S; de Almeida, R P; de Jesus, A R

    2017-07-01

    It is well established that helper T cell responses influence resistance or susceptibility to Mycobacterium leprae infection, but the role of more recently described helper T cell subsets in determining severity is less clear. To investigate the involvement of Th17 cells in the pathogenesis of leprosy, we determined the immune profile with variant presentations of leprosy. Firstly, IL-17A, IFN-γ and IL-10 were evaluated in conjunction with CD4 + T cell staining by confocal microscopy of lesion biopsies from tuberculoid (TT) and lepromatous leprosy (LL) patients. Secondly, inflammatory cytokines were measured by multiplex assay of serum samples from Multibacillary (MB, n = 28) and Paucibacillary (PB, n = 23) patients and household contacts (HHC, n = 23). Patients with leprosy were also evaluated for leprosy reaction occurrence: LR+ (n = 8) and LR- (n = 20). Finally, peripheral blood mononuclear cells were analysed by flow cytometry used to determine the phenotype of cytokine-producing cells. Lesions from TT patients were found to have more CD4 + IL-17A + cells than those from LL patients. Higher concentrations of IL-17A and IL-1β were observed in serum from PB than MB patients. The highest serum IFN-γ concentrations were, however, detected in sera from MB patients that developed leprosy reactions (MB LR + ). Together, these results indicate that Th1 cells were associated with both the PB presentation and also with leprosy reactions. In contrast, Th17 cells were associated with an effective inflammatory response that is present in the PB forms but were not predictive of leprosy reactions in MB patients. © 2017 The Foundation for the Scandinavian Journal of Immunology.

  11. Liposome delivery of Chlamydia muridarum major outer membrane protein primes a Th1 response that protects against genital chlamydial infection in a mouse model

    DEFF Research Database (Denmark)

    Hansen, Jon; Jensen, Klaus Thorleif; Follmann, Frank

    2008-01-01

    reported as being important for raising protective immunity. METHODS: C57BL/6 mice vaccinated with native refolded Chlamydia muridarum major outer membrane protein (MOMP) adjuvanted with either Th1-promoting cationic adjuvant formulation 1 (CAF01) or T helper cells type 2-promoting aluminum hydroxide (alum......BACKGROUND: Immunity to chlamydia is thought to rely on interferon (IFN)-gamma-secreting T helper cells type 1 (Th1) with an additional effect of secreted antibodies. A need for Th1-polarizing adjuvants in experimental chlamydia vaccines has been demonstrated, and antigen conformation has also been......) received a genital inoculation of 1.5 x 10(5) inclusion-forming units of C. muridarum. The role played by CD4(+) T cells in MOMP/CAF01-raised immunity was investigated by depleting CD4(+) T cells in vaccinated mice, and antigen conformation dependence was evaluated by vaccination with recombinant MOMP...

  12. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade

    Science.gov (United States)

    Stojanov, Silvia; Lapidus, Sivia; Chitkara, Puja; Feder, Henry; Salazar, Juan C.; Fleisher, Thomas A.; Brown, Margaret R.; Edwards, Kathryn M.; Ward, Michael M.; Colbert, Robert A.; Sun, Hong-Wei; Wood, Geryl M.; Barham, Beverly K.; Jones, Anne; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela; Athreya, Balu; Barron, Karyl S.; Kastner, Daniel L.

    2011-01-01

    The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever disease in children. However, the pathogenesis is unknown. Using a systems biology approach we analyzed blood samples from PFAPA patients whose genetic testing excluded hereditary periodic fevers (HPFs), and from healthy children and pediatric HPF patients. Gene expression profiling could clearly distinguish PFAPA flares from asymptomatic intervals, HPF flares, and healthy controls. During PFAPA attacks, complement (C1QB, C2, SERPING1), IL-1–related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes were significantly overexpressed, but T cell-associated transcripts (CD3, CD8B) were down-regulated. On the protein level, PFAPA flares were accompanied by significantly increased serum levels of chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9), G-CSF, and proinflammatory cytokines (IL-18, IL-6). PFAPA flares also manifested a relative lymphopenia. Activated CD4+/CD25+ T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4+/HLA-DR+ T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist. Based on the evidence for IL-1β activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist. All patients showed a prompt clinical and IP-10/CXCL10 response. Our data suggest an environmentally triggered activation of complement and IL-1β/-18 during PFAPA flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential biomarker. PMID:21478439

  13. Antibody Production and Th1-biased Response Induced by an Epitope Vaccine Composed of Cholera Toxin B Unit and Helicobacter pylori Lpp20 Epitopes.

    Science.gov (United States)

    Li, Yan; Chen, Zhongbiao; Ye, Jianbin; Ning, Lijun; Luo, Jun; Zhang, Lili; Jiang, Yin; Xi, Yue; Ning, Yunshan

    2016-06-01

    The epitope vaccine is an attractive potential for prophylactic and therapeutic vaccination against Helicobacter pylori (H. pylori) infection. Lpp20 is one of major protective antigens which trigger immune response after H. pylori invades host and has been considered as an excellent vaccine candidate for the control of H. pylori infection. In our previous study, one B-cell epitope and two CD4(+) T-cell epitopes of Lpp20 were identified. In this study, an epitope vaccine composed of mucosal adjuvant cholera toxin B subunit (CTB) and these three identified Lpp20 epitopes were constructed to investigate the efficacy of this epitope vaccine in mice. The epitope vaccine including CTB, one B-cell, and two CD4(+) T-cell epitopes of Lpp20 was constructed and named CTB-Lpp20, which was then expressed in Escherichia coli and used for intraperitoneal immunization in BALB/c mice. The immunogenicity, specificity, and ability to induce antibodies against Lpp20 and cytokine secretion were evaluated. After that, CTB-Lpp20 was intragastrically immunized to investigate the prophylactic and therapeutic efficacy in infected mice. The results indicated that the epitope vaccine CTB-Lpp20 possessed good immunogenicity and immunoreactivity and could elicit specific high level of antibodies against Lpp20 and the cytokine of IFN-γ and IL-17. Additionally, CTB-Lpp20 significantly decreased H. pylori colonization in H. pylori challenging mice, and the protection was correlated with IgG, IgA, and sIgA antibody and Th1-type cytokines. This study will be better for understanding the protective immunity of epitope vaccine, and CTB-Lpp20 may be an alternative strategy for combating H. pylori invasion. © 2015 John Wiley & Sons Ltd.

  14. Ferulic Acid Induces Th1 Responses by Modulating the Function of Dendritic Cells and Ameliorates Th2-Mediated Allergic Airway Inflammation in Mice

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    Chen-Chen Lee

    2015-01-01

    Full Text Available This study investigated the immunomodulatory effects of ferulic acid (FA on antigen-presenting dendritic cells (DCs in vitro and its antiallergic effects against ovalbumin- (OVA- induced Th2-mediated allergic asthma in mice. The activation of FA-treated bone marrow-derived DCs by lipopolysaccharide (LPS stimulation induced a high level of interleukin- (IL- 12 but reduced the expression levels of the proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor- (TNF- α. Compared to control-treated DCs, FA significantly enhanced the expressions of Notch ligand Delta-like 4 (Dll4, MHC class II, and CD40 molecules by these DCs. Furthermore, these FA-treated DCs enhanced T-cell proliferation and Th1 cell polarization. In animal experiments, oral administration of FA reduced the levels of OVA-specific immunoglobulin E (IgE and IgG1 and enhanced IgG2a antibody production in serum. It also ameliorated airway hyperresponsiveness and attenuated eosinophilic pulmonary infiltration in dose-dependent manners. In addition, FA treatment inhibited the production of eotaxin, Th2 cytokines (IL-4, IL-5, and IL-13, and proinflammatory cytokines but promoted the Th1 cytokine interferon- (IFN- γ production in bronchoalveolar lavage fluid (BALF and the culture supernatant of spleen cells. These findings suggest that FA exhibits an antiallergic effect via restoring Th1/Th2 imbalance by modulating DCs function in an asthmatic mouse model.

  15. Dichotomy of the human T cell response to Leishmania antigens. I. Th1-like response to Leishmania major promastigote antigens in individuals recovered from cutaneous leishmaniasis

    DEFF Research Database (Denmark)

    Kemp, M; Hey, A S; Kurtzhals, J A

    1994-01-01

    The T cell response to antigens from Leishmania major promastigotes was investigated in peripheral blood mononuclear cells from Sudanese individuals with a history of cutaneous leishmaniasis (CL), Sudanese individuals with positive DTH reaction in the leishmanin skin test but with no history...

  16. Reduction of IL-17A Might Suppress the Th1 Response and Promote the Th2 Response by Boosting the Function of Treg Cells during Silica-Induced Inflammatory Response In Vitro

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    Wen Tang

    2014-01-01

    Full Text Available Silica inhalation can induce chronic lung inflammation and fibrosis. Upon silica stimulation, activated macrophages trigger the T-lymphocyte which can differentiate into many different types of Th cells, including the recently discovered Th17 cells. IL-17A, the typical Th17 cytokine, is reported in some inflammatory diseases. However, the role of IL-17A in silica-induced inflammatory response is still not clear. The regulatory mechanism of silica-induced Th17 response also needs to be investigated. So we established a mice primary cell coculture system (macrophage and lymphocyte to investigate the role of IL-17A in silica-induced inflammatory response in vitro, by using anti-IL-17A mAb and IL-1Ra. Both anti-IL-17A mAb and IL-1Ra decreased the level of IL-17A and increased the function of Treg cells. The Th1 response was suppressed and the Th2 response was promoted by the addition of anti-IL-17A mAb or IL-1Ra. IL-1Ra treatment decreased the level of IL-6, whereas the levels of IL-23 and ROR-γt were increased. Our study demonstrated that IL-17A reduction altered the pattern of silica-induced Th responses by boosting the function of Treg cells in vitro. Blocking the function of IL-1 signal pathway could suppress the level of IL-17A, which played the major role in modulating silica-induced Th responses in vitro.

  17. Induction of a T-Helper 1 (Th1) Immune Response in Mice by an Extract from the Pleurotus eryngii (Eringi) Mushroom

    Science.gov (United States)

    Kameyama, Natsuko; Ito, Akira; Imai, Soichi

    2012-01-01

    Abstract To assess the effect of edible mushroom extracts on the induction of T-helper 1 (Th1) immunity, we examined differences in interferon-gamma (IFN-γ) and interleukin (IL)-4 production in mice induced by hot-water extracts of 15 species of edible mushroom. Extracts from Agaricus bisporus, Flammulina velutipes, Hypsizigus marmoreus, Lentinula edodes, and Lyophyllum decastes induced both IFN-γ and IL-4 production in mice, whereas extracts from Pleurotus ostreatus only induced IL-4. In contrast, extracts from Agaricus blazei, Grifola frondosa, Morchella esculenta, Pholiota nameko, Pleurotus citrinopileatus, and Pleurotus eryngii induced only IFN-γ production. In particular, the extract from P. eryngii induced high levels of IFN-γ and reduced levels of IL-4. We further investigated the use of a trial immunogen using the P. eryngii extract as a Th1 immunostimulator. An oil-in-water emulsion of the hot-water extract from P. eryngii (immunostimulator) and ovalbumin (OVA; antigen) was used as a trial immunogen. This immunogen induced strong OVA-specific IgG2a antibody production in mice compared with the negative controls. In addition, OVA-specific IgG1 antibody levels were lower than those for the negative controls. Marked increases in serum IFN-γ levels and high-level production of IFN-γ in the culture supernatant from the CD4+ spleen cells in the trial immunogen group mice were observed. Our results suggested that the hot-water extract from P. eryngii induced Th1 immunity by acting as an immunostimulator. PMID:23134464

  18. Gender-specific effects of genetic variants within Th1 and Th17 cell-mediated immune response genes on the risk of developing rheumatoid arthritis.

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    Rafael Cáliz

    Full Text Available The present study was conducted to explore whether single nucleotide polymorphisms (SNPs in Th1 and Th17 cell-mediated immune response genes differentially influence the risk of rheumatoid arthritis (RA in women and men. In phase one, 27 functional/tagging polymorphisms in C-type lectins and MCP-1/CCR2 axis were genotyped in 458 RA patients and 512 controls. Carriers of Dectin-2 rs4264222T allele had an increased risk of RA (OR = 1.47, 95%CI 1.10-1.96 whereas patients harboring the DC-SIGN rs4804803G, MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of developing the disease (OR = 0.66, 95%CI 0.49-0.88; OR = 0.66, 95%CI 0.50-0.89; OR = 0.73, 95%CI 0.55-0.97 and OR = 0.68, 95%CI 0.51-0.91. Interestingly, significant gender-specific differences were observed for Dectin-2 rs4264222 and Dectin-2 rs7134303: women carrying the Dectin-2 rs4264222T and Dectin-2 rs7134303G alleles had an increased risk of RA (OR = 1.93, 95%CI 1.34-2.79 and OR = 1.90, 95%CI 1.29-2.80. Also five other SNPs showed significant associations only with one gender: women carrying the MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of RA (OR = 0.61, 95%CI 0.43-0.87; OR = 0.67, 95%CI 0.47-0.95 and OR = 0.60, 95%CI 0.42-0.86. In men, carriers of the DC-SIGN rs2287886A allele had an increased risk of RA (OR = 1.70, 95%CI 1.03-2.78, whereas carriers of the DC-SIGN rs4804803G had a decreased risk of developing the disease (OR = 0.53, 95%CI 0.32-0.89. In phase 2, we genotyped these SNPs in 754 RA patients and 519 controls, leading to consistent gender-specific associations for Dectin-2 rs4264222, MCP-1 rs1024611, MCP-1 rs13900 and DC-SIGN rs4804803 polymorphisms in the pooled sample (OR = 1.38, 95%CI 1.08-1.77; OR = 0.74, 95%CI 0.58-0.94; OR = 0.76, 95%CI 0.59-0.97 and OR = 0.56, 95%CI 0.34-0.93. SNP-SNP interaction analysis of significant SNPs also showed a

  19. Gender-specific effects of genetic variants within Th1 and Th17 cell-mediated immune response genes on the risk of developing rheumatoid arthritis.

    Science.gov (United States)

    Cáliz, Rafael; Canet, Luz María; Lupiañez, Carmen Belén; Canhão, Helena; Escudero, Alejandro; Filipescu, Ileana; Segura-Catena, Juana; Soto-Pino, María José; Expósito-Ruiz, Manuela; Ferrer, Miguel Ángel; García, Antonio; Romani, Lurdes; González-Utrilla, Alfonso; Vallejo, Teresa; Pérez-Pampin, Eva; Hemminki, Kari; Försti, Asta; Collantes, Eduardo; Fonseca, João Eurico; Sainz, Juan

    2013-01-01

    The present study was conducted to explore whether single nucleotide polymorphisms (SNPs) in Th1 and Th17 cell-mediated immune response genes differentially influence the risk of rheumatoid arthritis (RA) in women and men. In phase one, 27 functional/tagging polymorphisms in C-type lectins and MCP-1/CCR2 axis were genotyped in 458 RA patients and 512 controls. Carriers of Dectin-2 rs4264222T allele had an increased risk of RA (OR = 1.47, 95%CI 1.10-1.96) whereas patients harboring the DC-SIGN rs4804803G, MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of developing the disease (OR = 0.66, 95%CI 0.49-0.88; OR = 0.66, 95%CI 0.50-0.89; OR = 0.73, 95%CI 0.55-0.97 and OR = 0.68, 95%CI 0.51-0.91). Interestingly, significant gender-specific differences were observed for Dectin-2 rs4264222 and Dectin-2 rs7134303: women carrying the Dectin-2 rs4264222T and Dectin-2 rs7134303G alleles had an increased risk of RA (OR = 1.93, 95%CI 1.34-2.79 and OR = 1.90, 95%CI 1.29-2.80). Also five other SNPs showed significant associations only with one gender: women carrying the MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of RA (OR = 0.61, 95%CI 0.43-0.87; OR = 0.67, 95%CI 0.47-0.95 and OR = 0.60, 95%CI 0.42-0.86). In men, carriers of the DC-SIGN rs2287886A allele had an increased risk of RA (OR = 1.70, 95%CI 1.03-2.78), whereas carriers of the DC-SIGN rs4804803G had a decreased risk of developing the disease (OR = 0.53, 95%CI 0.32-0.89). In phase 2, we genotyped these SNPs in 754 RA patients and 519 controls, leading to consistent gender-specific associations for Dectin-2 rs4264222, MCP-1 rs1024611, MCP-1 rs13900 and DC-SIGN rs4804803 polymorphisms in the pooled sample (OR = 1.38, 95%CI 1.08-1.77; OR = 0.74, 95%CI 0.58-0.94; OR = 0.76, 95%CI 0.59-0.97 and OR = 0.56, 95%CI 0.34-0.93). SNP-SNP interaction analysis of significant SNPs also showed a significant

  20. Altered Macrophage and Dendritic Cell Response in Mif−/− Mice Reveals a Role of Mif for Inflammatory-Th1 Response in Type 1 Diabetes

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    Yuriko Itzel Sánchez-Zamora

    2016-01-01

    Full Text Available Macrophage migration inhibitory factor (Mif is highly expressed in type 1 diabetes mellitus (T1DM. However, there is limited information about how Mif influences the activation of macrophages (Mφ and dendritic cells (DC in T1DM. To address this issue, we induced T1DM by administering multiple low doses of streptozotocin (STZ to Mif−/− or wild-type (Wt BALB/c mice. We found that Mif−/− mice treated with STZ (Mif−/−STZ developed lower levels of hyperglycemia, inflammatory cytokines, and specific pancreatic islet antigen- (PIAg- IgG and displayed reduced cellular infiltration into the pancreatic islets compared to Wt mice treated with STZ (WtSTZ. Moreover, Mφ and DC from Mif−/−STZ displayed lower expression of MHC-II, costimulatory molecules CD80, CD86, and CD40, Toll-like receptor- (TLR- 2, and TLR-4 than WtSTZ. These changes were associated with a reduced capacity of Mφ and DC from Mif−/−STZ to induce proliferation in ovalbumin-specific T cells. All the deficiencies observed in Mif−/−STZ were recovered by exogenous administration of recombinant Mif. These findings suggest that Mif plays a role in the molecular mechanisms of Mφ and DC activation and drives T cell responses involved in the pathology of T1DM. Therefore, Mif is a potential therapeutic target to reduce the pathology of T1DM.

  1. Altered Macrophage and Dendritic Cell Response in Mif−/− Mice Reveals a Role of Mif for Inflammatory-Th1 Response in Type 1 Diabetes

    Science.gov (United States)

    Vazquez-Mendoza, Alicia

    2016-01-01

    Macrophage migration inhibitory factor (Mif) is highly expressed in type 1 diabetes mellitus (T1DM). However, there is limited information about how Mif influences the activation of macrophages (Mφ) and dendritic cells (DC) in T1DM. To address this issue, we induced T1DM by administering multiple low doses of streptozotocin (STZ) to Mif−/− or wild-type (Wt) BALB/c mice. We found that Mif−/− mice treated with STZ (Mif−/−STZ) developed lower levels of hyperglycemia, inflammatory cytokines, and specific pancreatic islet antigen- (PIAg-) IgG and displayed reduced cellular infiltration into the pancreatic islets compared to Wt mice treated with STZ (WtSTZ). Moreover, Mφ and DC from Mif−/−STZ displayed lower expression of MHC-II, costimulatory molecules CD80, CD86, and CD40, Toll-like receptor- (TLR-) 2, and TLR-4 than WtSTZ. These changes were associated with a reduced capacity of Mφ and DC from Mif−/−STZ to induce proliferation in ovalbumin-specific T cells. All the deficiencies observed in Mif−/−STZ were recovered by exogenous administration of recombinant Mif. These findings suggest that Mif plays a role in the molecular mechanisms of Mφ and DC activation and drives T cell responses involved in the pathology of T1DM. Therefore, Mif is a potential therapeutic target to reduce the pathology of T1DM. PMID:27699180

  2. Th1 stimulatory proteins of Leishmania donovani: comparative cellular and protective responses of rTriose phosphate isomerase, rProtein disulfide isomerase and rElongation factor-2 in combination with rHSP70 against visceral leishmaniasis.

    Science.gov (United States)

    Jaiswal, Anil Kumar; Khare, Prashant; Joshi, Sumit; Kushawaha, Pramod Kumar; Sundar, Shyam; Dube, Anuradha

    2014-01-01

    In visceral leishmaniasis, the recovery from the disease is always associated with the generation of Th1-type of cellular responses. Based on this, we have previously identified several Th1-stimulatory proteins of Leishmania donovani -triose phosphate isomerase (TPI), protein disulfide isomerase (PDI) and elongation factor-2 (EL-2) etc. including heat shock protein 70 (HSP70) which induced Th1-type of cellular responses in both cured Leishmania patients/hamsters. Since, HSPs, being the logical targets for vaccines aimed at augmenting cellular immunity and can be early targets in the immune response against intracellular pathogens; they could be exploited as vaccine/adjuvant to induce long-term immunity more effectively. Therefore, in this study, we checked whether HSP70 can further enhance the immunogenicity and protective responses of the above said Th1-stimulatory proteins. Since, in most of the studies, immunogenicity of HSP70 of L. donovani was assessed in native condition, herein we generated recombinant HSP70 and tested its potential to stimulate immune responses in lymphocytes of cured Leishmania infected hamsters as well as in the peripheral blood mononuclear cells (PBMCs) of cured patients of VL either individually or in combination with above mentioned recombinant proteins. rLdHSP70 alone elicited strong cellular responses along with remarkable up-regulation of IFN-γ and IL-12 cytokines and extremely lower level of IL-4 and IL-10. Among the various combinations, rLdHSP70 + rLdPDI emerged as superior one augmenting improved cellular responses followed by rLdHSP70 + rLdEL-2. These combinations were further evaluated for its protective potential wherein rLdHSP70 + rLdPDI again conferred utmost protection (∼80%) followed by rLdHSP70 + rLdEL-2 (∼75%) and generated a strong cellular immune response with significant increase in the levels of iNOS transcript as well as IFN-γ and IL-12 cytokines which was further supported by the high level of IgG2 antibody

  3. Th1/Th2 balance and humoral immune response to potential antigens as early diagnostic method of equine Strongylus nematode infection

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    Faten A. M. Abo-Aziza

    2017-06-01

    Full Text Available Aim: The aim of this study was to investigate the early diagnosis of strongyle infection based on early changes in Th1 and Th2 cytokines beside the diagnostic accuracy values and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE and western blotting profiles using prepared strongyles antigens. Materials and Methods: A total of 73 donkeys had a mean age of 4-32 years old were parasitologically examined for strongyle infection. The early changes in Th1 and Th2 cytokines were determined, and the diagnostic accuracy values and SDS-PAGE and western blotting profiles were performed using prepared strongyles antigens; crude somatic Strongylus vulgaris (CSS, excretory-secretory S. vulgaris (ESS, crude somatic Cyathostomins (CSC, and excretory-secretory Cyathostomins (ESC. Results: The results revealed highest 437.04% and lowest 37.81% immunoglobulin G (IgG in high and low egg shedder groups when using ESC and CSS antigens, respectively. Antibodies index for ESS and CSC were significantly higher in moderate egg shedder group while that for ESS and CSC, ESC was significantly higher in high egg shedder group. Tumor necrosis factor alpha (TNF-α/interleukin-4 (IL-4 balance in S. vulgaris infected donkeys was approximately equal in apparently healthy, low and high egg shedder groups while TNF-α < IL-4 in moderate egg shedder. In Cyathostomins infected animals, TNF-α/IL-4 balance was approximately equal in apparently healthy group while it was low in moderate and high egg shedder groups. The diagnostic accuracy showed that the higher specificity (46.6% and prevalence (95.40% were recorded by CSS and ESC antigens, respectively. However, SDS-PAGE and western blotting profiling proved that the band at molecular weight 25 kDa is exhibited by CSS antigen. Conclusion: Combination of detecting level of TNF-α/IL-4 balance, CSS antigen and IgG concentration is good tool for appropriate diagnosis of such infection. More advancement research must be

  4. Enhanced Th1 and Th2 immune response induction by Human Papilloma virus Type 16 E7 DNA vaccine in a tumoric murine model

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    Alireza Mohebbi

    2017-01-01

    Full Text Available Background and Objectives: Human papilloma virus (HPV is known as the etiologic agent of cervical cancer and second common cancer among women. HPV viruses with the elevated risk of infection have more potentiality to cause cancer. The carcinogenesis in these viruses is accomplished by oncoproteins such as E7. Employing DNA vaccines which code specific antigens such as E7 is a novel therapeutic approach against such cancers. Methods: In the present study, plasmid coding HPV16 E7 was administered intracutaneously to C57BL/6 tumoric mice models for investigation of its immunostimulating potential. PcDNA3.1+ vector was used as control vector. After immunization, spleen of animals were removed. Then, release of lactate dehydrogenase (LDH was evaluated to address the cytotoxic activity (CTL induced by cellular immunity in spleenocytes. Interferon-γ (IFN-γ and interleukin-4 (IL-4 cytokines were also analyzed as profiles of Th1 and Th2, respectively. Anti-inflammatory cytokine interleukin-10 (IL-10 levels were also investigated in tumor microenvironments. Results: Our results showed that CTL activity was higher among samples receiving HPV16 E7 coding vector in comparison to the group receiving pcDNA3.1+ control vector (P < 0.05. Levels of IFN-γ and IL-4 were also higher in the group receiving HPV16 E7 plasmid in comparison to the control group (P < 0.05. Similarly, IL-10 levels were significantly lower in tumor carrying mice groups receiving HPV16 DNA vaccine compare to PBS and pcDNA3.1 receiving control groups. Conclusion: HPV16 E7 expressing DNA vaccine could increase the release of LDH due to immune system CTL activity. Elevation in IFN-γ and IL-4 levels as well as IL-10 reduction indicates an increase in both Th1 and Th2 profiles resulted by using potent DNA vaccine coding HPV16 E7 in tumor animal model.

  5. Myocardial Gene Expression of T-bet, GATA-3, Ror-γt, FoxP3, and Hallmark Cytokines in Chronic Chagas Disease Cardiomyopathy: An Essentially Unopposed TH1-Type Response

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    Luciana Gabriel Nogueira

    2014-01-01

    Full Text Available Background. Chronic Chagas disease cardiomyopathy (CCC, a late consequence of Trypanosoma cruzi infection, is an inflammatory cardiomyopathy with prognosis worse than those of noninflammatory etiology (NIC. Although the T cell-rich myocarditis is known to play a pathogenetic role, the relative contribution of each of the functional T cell subsets has never been thoroughly investigated. We therefore assessed gene expression of cytokines and transcription factors involved in differentiation and effector function of each functional T cell subset (TH1/TH2/TH17/Treg in CCC, NIC, and heart donor myocardial samples. Methods and Results. Quantitative PCR showed markedly upregulated expression of IFN-γ and transcription factor T-bet, and minor increases of GATA-3; FoxP3 and CTLA-4; IL-17 and IL-18 in CCC as compared with NIC samples. Conversely, cytokines expressed by TH2 cells (IL-4, IL-5, and IL-13 or associated with Treg (TGF-β and IL-10 were not upregulated in CCC myocardium. Expression of TH1-related genes such as T-bet, IFN-γ, and IL-18 correlated with ventricular dilation, FoxP3, and CTLA-4. Conclusions. Results are consistent with a strong local TH1-mediated response in most samples, possibly associated with pathological myocardial remodeling, and a proportionally smaller FoxP3+CTLA4+ Treg cell population, which is unable to completely curb IFN-γ production in CCC myocardium, therefore fueling inflammation.

  6. Oral vaccination with a recombinant Salmonella vaccine vector provokes systemic HIV-1 subtype C Gag-specific CD4+ Th1 and Th2 cell immune responses in mice

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    Williamson Anna-Lise

    2009-06-01

    Full Text Available Abstract Background Recombinant Salmonella vaccine vectors may potentially be used to induce specific CD4+ T cell responses against foreign viral antigens. Such immune responses are required features of vaccines against pathogens such as human immunodeficiency virus type 1 (HIV-1. The aim of this study was to investigate the induction of systemic HIV-1-specific CD4+ T helper (Th responses in mice after oral immunization with a live attenuated Salmonella vaccine vector that expressed HIV-1 subtype C Gag. Groups of BALB/c mice were vaccinated orally three times (4 weeks apart with this recombinant Salmonella. At sacrifice, 28 days after the last immunization, systemic CD4+ Th1 and Th2 cytokine responses were evaluated by enzyme-linked immunospot assay and cytometric bead array. HIV-1 Gag-specific IgG1 and IgG2a humoral responses in the serum were determined by enzyme-linked immunosorbent assay. Results Mice vaccinated with the recombinant Salmonella elicited both HIV-1-specific Th1 (interferon-gamma (IFN-γ and tumour necrosis factor-alpha (TNF-α and Th2 (interleukin-4 (IL-4 and interleukin-5 (IL-5 cytokine responses. The vaccine induced 70 (IFN-γ spot-forming units (SFUs/10e6 splenocytes and 238 IL-4 SFUs/10e6 splenocytes. Splenocytes from vaccinated mice also produced high levels of Th1 and Th2 cytokines upon stimulation with a Gag CD4 peptide. The levels of IFN-γ, TNF-α, IL-4 and IL-5 were 7.5-, 29.1-, 26.2- and 89.3-fold above the background, respectively. Both HIV-1 Gag-specific IgG1 and IgG2a antibodies were detected in the sera of vaccinated mice. Conclusion The study highlights the potential of orally-delivered attenuated Salmonella as mucosal vaccine vectors for HIV-1 Subtype C Gag to induce Gag-specific CD4+ Th1 and Th2 cellular immune responses and antibodies which may be important characteristics required for protection against HIV-1 infection.

  7. Construction, purification, and characterization of a chimeric TH1 antagonist

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    Javier-González Luís

    2006-05-01

    Full Text Available Abstract Background TH1 immune response antagonism is a desirable approach to mitigate some autoimmune and inflammatory reactions during the course of several diseases where IL-2 and IFN-γ are two central players. Therefore, the neutralization of both cytokines could provide beneficial effects in patients suffering from autoimmune or inflammatory illnesses. Results A chimeric antagonist that can antagonize the action of TH1 immunity mediators, IFN-γ and IL-2, was designed, engineered, expressed in E. coli, purified and evaluated for its in vitro biological activities. The TH1 antagonist molecule consists of the extracellular region for the human IFNγ receptor chain 1 fused by a four-aminoacid linker peptide to human 60 N-terminal aminoacid residues of IL-2. The corresponding gene fragments were isolated by RT-PCR and cloned in the pTPV-1 vector. E. coli (W3110 strain was transformed with this vector. The chimeric protein was expressed at high level as inclusion bodies. The protein was partially purified by pelleting and washing. It was then solubilized with strong denaturant and finally refolded by gel filtration. In vitro biological activity of chimera was demonstrated by inhibition of IFN-γ-dependent HLA-DR expression in Colo 205 cells, inhibition of IFN-γ antiproliferative effect on HEp-2 cells, and by a bidirectional effect in assays for IL-2 T-cell dependent proliferation: agonism in the absence versus inhibition in the presence of IL-2. Conclusion TH1 antagonist is a chimeric protein that inhibits the in vitro biological activities of human IFN-γ, and is a partial agonist/antagonist of human IL-2. With these attributes, the chimera has the potential to offer a new opportunity for the treatment of autoimmune and inflammatory diseases.

  8. Mycobacterium tuberculosis Latent Antigen Rv2029c from the Multistage DNA Vaccine A39 Drives TH1 Responses via TLR-mediated Macrophage Activation

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    Haibo Su

    2017-11-01

    Full Text Available Targeting of Mycobacterium tuberculosis (MTB latent antigens comprises a crucial strategy for the development of alternative tuberculosis (TB vaccine(s that protects against TB reactivation. Here, we generated a multistage DNA vaccine, A39, containing the early antigens Ag85A and Rv3425 as well as the latency-associated protein Rv2029c, which conferred protective immunity in a pre-exposure mouse model. Moreover, administration of the A39 vaccination after MTB exposure inhibited reactivation and resulted in significantly lower bacterial loads in the lungs and spleen of mice, compared to those in the control population. Subsequently, we investigated the effect of Rv2029c on innate immunity and characterized the molecular details of the interaction of this protein with the host via iTRAQ proteomic and biochemical assay analyses. Rv2029c activated macrophages, triggered the production of pro-inflammatory cytokines, and promoted toll-like receptor/mitogen-activated protein kinase (TLR/MAPK-dependent macrophage apoptosis. Furthermore, Rv2029c treatment enhanced the ability of Mycobacterium bovis Bacillus Calmette-Guérin (BCG-infected macrophages to present antigens to CD4+ T cells in vitro, which correlated with an increase in MHC-II expression. Lastly, Rv2029c-treated macrophages activated T cells, effectively polarized CD4+ and CD8+ T cells to secrete IFN-γ and IL-2, and specifically expanded a population of CD44highCD62LlowCD4+/CD8+ effector/memory cells, indicating that Rv2029c, as a specific recall antigen, contributes to Th1 polarization in T cell immunity. These results suggest that Rv2029c and A39 comprise promising targets for the development of next-generation clinical TB therapeutic vaccines.

  9. Mucosal Administration of CpG Oligodeoxynucleotide Elicits Strong CC and CXC Chemokine Responses in the Vagina and Serves as a Potent Th1-Tilting Adjuvant for Recombinant gD2 Protein Vaccination against Genital Herpes

    Science.gov (United States)

    Tengvall, Sara; Lundqvist, Annika; Eisenberg, Roselyn J.; Cohen, Gary H.; Harandi, Ali M.

    2006-01-01

    Although sexually transmitted pathogens are capable of inducing pathogen-specific immune responses, vaginal administration of nonreplicating antigens elicits only weak, nondisseminating immune responses. The present study was undertaken to examine the potential of CpG-containing oligodeoxynucleotide (CpG ODN) for induction of chemokine responses in the genital tract mucosa and also as a vaginal adjuvant in combination with glycoprotein D of herpes simplex virus type 2 (HSV-2) for induction of antigen-specific immune responses. We found that a single intravaginal administration of CpG ODN in mice stimulates a rapid and potent response of CC chemokines macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and RANTES as well as of CXC chemokines MIP-2 and IP-10 in the vagina and/or the genital lymph nodes. Importantly, intravaginal vaccination with recombinant gD2 in combination with CpG ODN gave rise to a strong antigen-specific Th1-like immune response in the genital lymph nodes as well as the spleens of the vaccinated mice. Further, such an immunization scheme conferred both systemic and mucosal immunoglobulin G antibody responses as well as protection against an otherwise lethal vaginal challenge with HSV-2. These results illustrate the potential of CpG ODN for induction of potent chemokine responses in the genital tract and also as a vaginal adjuvant for generation of Th1-type mucosal and systemic immune responses towards a nonreplicating antigen derived from a sexually transmitted pathogen. These data have implications for the development of a mucosal vaccine against genital herpes and possibly other sexually transmitted diseases. PMID:16699008

  10. Poly(I:C) adjuvant strongly enhances parasite-inhibitory antibodies and Th1 response against Plasmodium falciparum merozoite surface protein-1 (42-kDa fragment) in BALB/c mice.

    Science.gov (United States)

    Mehrizi, Akram Abouie; Rezvani, Niloufar; Zakeri, Sedigheh; Gholami, Atefeh; Babaeekhou, Laleh

    Malaria vaccine development has been confronted with various challenges such as poor immunogenicity of malaria vaccine candidate antigens, which is considered as the main challenge. However, this problem can be managed using appropriate formulations of antigens and adjuvants. Poly(I:C) is a potent Th1 inducer and a human compatible adjuvant capable of stimulating both B- and T-cell immunity. Plasmodium falciparum merozoite surface protein 142 (PfMSP-142) is a promising vaccine candidate for blood stage of malaria that has faced several difficulties in clinical trials, mainly due to improper adjuvants. Therefore, in the current study, poly(I:C), as a potent Th1 inducer adjuvant, was evaluated to improve the immunogenicity of recombinant PfMSP-142, when compared to CFA/IFA, as reference adjuvant. Poly(I:C) produced high level and titers of anti-PfMSP-142 IgG antibodies in which was comparable to CFA/IFA adjuvant. In addition, PfMSP-142 formulated with poly(I:C) elicited a higher ratio of IFN-γ/IL-4 (23.9) and IgG2a/IgG1 (3.77) with more persistent, higher avidity, and titer of IgG2a relative to CFA/IFA, indicating a potent Th1 immune response. Poly(I:C) could also help to induce anti-PfMSP-142 antibodies with higher growth-inhibitory activity than CFA/IFA. Altogether, the results of the current study demonstrated that poly(I:C) is a potent adjuvant that can be appropriate for being used in PfMSP-142-based vaccine formulations.

  11. Dichotomy of the T cell response to Leishmania antigens in patients suffering from cutaneous leishmaniasis; absence or scarcity of Th1 activity is associated with severe infections

    DEFF Research Database (Denmark)

    Gaafar, A; Kharazmi, A; Ismail, A

    1995-01-01

    The T cell response was studied in 25 patients suffering from cutaneous leishmaniasis caused by Leishmania major with severe (n = 10) and mild (n = 15) disease manifestations. Peripheral blood mononuclear cells (PBMC) from the patients were activated by sonicates of Leishmania promastigotes (LMP...

  12. Mononuclear cells from patients recovered from cutaneous leishmaniasis respond to Leishmania major amastigote class I nuclease with a predominant Th1-like response

    Science.gov (United States)

    Farajnia, S; Mahboudi, F; Ajdari, S; Reiner, N E; Kariminia, A; Alimohammadian, M H

    2005-01-01

    The Leishmania major amastigote class I nuclease (LmaCIN) is a developmentally regulated protein that is highly expressed in the amastigote stage of L. major. This protein is homologous to the P4 nuclease of L. pifanoi, which has been shown to induce protective immune response in a murine model. To evaluate LmaCIN as a potential human vaccine candidate, cellular immune responses to recombinant LmaCIN were examined in individuals recovered from Old World cutaneous leishmaniasis. Peripheral blood mononuclear cells (PBMC) from patients recovered from L. major infection were cultured either with recombinant LmaCIN or autoclaved L. major (ALM) as control. rLmaCIN induced significant proliferation of PBMC from 90% of recovered patients. Phenotypic analysis of proliferating cells showed that CD8+ cells were the predominant cell type proliferating in response to rLmaC1N. Screening of culture supernatants for cytokines showed that rLmaCIN induced high levels of interferon (IFN)-γ (mean ± s.e.m.: 1398 ± 179 pg/ml) associated with little interleukin (IL)-10 and little or no IL-5 production. These findings show that LmaCIN is immunogenic in humans during L. major infection and that it can elicit immunological responses relevant to immunoprophylaxis of leishmaniasis. PMID:15730396

  13. Intestinal Irradiation and Fibrosis in a Th1-Deficient Environment

    Energy Technology Data Exchange (ETDEWEB)

    Linard, Christine, E-mail: christine.linard@irsn.fr [Institut de Radioprotection et de Surete Nucleaire, Fontenay-aux-Roses (France); Billiard, Fabienne; Benderitter, Marc [Institut de Radioprotection et de Surete Nucleaire, Fontenay-aux-Roses (France)

    2012-09-01

    Purpose: Changes in the Th1/Th2 immune balance may play a role in increasing the incidence of radiation-induced toxicity. This study evaluates the consequences of Th1 deficiency on intestinal response (fibrosis and T cell trafficking) to abdominal irradiation and examines in mucosa and mesenteric lymph nodes (MLN) the differential involvement of the two Th1 pathways, T-bet/STAT1 and IL-12/STAT4, in controlling this balance in mice. Methods and Materials: Using T-bet-deficient mice (T-bet{sup -/-}), we evaluated the mRNA and protein expression of the Th1 pathways (IFN-{gamma}, T-bet/STAT1, and IL-12/STAT4) and the CD4{sup +} and CD8{sup +} populations in ileal mucosa and MLN during the first 3 months after 10 Gy abdominal irradiation. Results: The T-bet-deficient mice showed an increased fibrotic response to radiation, characterized by higher TGF-{beta}1, col3a1 expression, and collagen deposition in mucosa compared with wild-type mice. This response was associated with drastically lower expression of IFN-{gamma}, the hallmark Th1 cytokine. Analysis of the Th1 expression pathways, T-bet/STAT1 and IL-12/STAT4, showed their equal involvement in the failure of Th1 polarization. A minimal IFN-{gamma} level depended on the IL-23-p19/STAT4 level. In addition, the radiation-induced deficiency in the priming of Th1 by IFN-{gamma} was related to the defective homing capacity of CD8{sup +} cells in the mucosa. Conclusion: Irradiation induces Th2 polarization, and the Th2 immune response may play a role in potentiating irradiation-induced intestinal collagen deposition.

  14. The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety.

    Science.gov (United States)

    Maes, M; Song, C; Lin, A; De Jongh, R; Van Gastel, A; Kenis, G; Bosmans, E; De Meester, I; Benoy, I; Neels, H; Demedts, P; Janca, A; Scharpé, S; Smith, R S

    1998-04-01

    There is some evidence that, in humans and experimental animals, psychological stress may suppress or enhance immune functions, depending on the nature of the stressor and the immune variables under consideration. The possibility that psychological stress may affect the production of pro-inflammatory and immunoregulatory cytokines was investigated in 38 medical students, who had blood samplings a few weeks before and after as well as one day before an academic examination. Psychological stress significantly increased the stimulated production of tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), IL-1 receptor antagonist (IL-1Ra), interferon gamma (IFN-gamma) and IL-10. Students with high stress perception during the stressful condition had a significantly higher production of TNF-alpha, IL-6, IL-1Ra and IFN-gamma than students with a low-stress perception. Students with a high anxiety response had a significantly higher production of IFN-gamma and a lower production of the negative immunoregulatory cytokines, IL-10 and IL-4, than students without anxiety. These findings suggest that, in humans, changes in the production of the pro-inflammatory cytokines, TNF-alpha, IL-6 and IFN-gamma, and negative immunoregulatory cytokines, IL-10 and IL-4, take part in the homeostatic responses to psychological stress and that stress-induced anxiety is related to a T-helper-1-like response.

  15. Immunization with Leishmania donovani protein disulfide isomerase DNA construct induces Th1 and Th17 dependent immune response and protection against experimental visceral leishmaniasis in Balb/c mice.

    Science.gov (United States)

    Amit, Ajay; Vijayamahantesh; Dikhit, Manas R; Singh, Ashish Kumar; Kumar, Vikash; Suman, Shashi S; Singh, Ashu; Kumar, Akhilesh; Thakur, Ajit Kumar; Das, Vidyanand Ravi; Das, Pradeep; Bimal, Sanjiva

    2017-02-01

    In the present study, the efficacy of Leishmania donovani protein disulfide isomerase (LdPDI) as a DNA vaccine was evaluated in BALB/C mice. Mice immunized with the LdPDI-DNA construct were found to be the most immuno-reactive, as the construct induced higher T-cell proliferation. The increased T-cell proliferation was associated with a substantial rise in Th1 and Th17+ CD4 cell response and triggered a higher proportion of CD8+ T cells for the release of interferon-gamma along with a reduced splenic parasite load on Days20 and 60 post challenge (PC). Furthermore, the vaccine construct triggered increased interferon (IFN)-γ, interleukin(IL)-17A, and IL-22 release accompanied by decreased extracellular signal-regulated kinases (ERK) 1/2 signaling and increased mitogen-activated protein kinase (MAPK) signaling coinciding with an increase in the amount of nitrite and reactive oxygen species (ROS)in vaccinating the splenocyts. We summarize from our data that the PDI-DNA construct of Leishmania donovani has the potential to elicit protective immunity through the pro-inflammatory cytokines of CD8+ and CD4+(Th1 and Th17) following an intervention in the downstream signaling event of ERK1/2 (probably through p38MAPK signaling). Therefore, the study suggests a new control against visceral leishmaniasis in the future. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Regulatory effects of Th1-type (IFN-γ, IL-12) and Th2-type cytokines (IL-10, IL-13) on parasite-specific cellular responsiveness in Onchocerca volvulus-infected humans and exposed endemic controls

    Science.gov (United States)

    Soboslay, P T; Lüder, C G K; Riesch, S; Geiger, S M; Banla, M; Batchassi, E; Stadler, A; Schulz-Key, H

    1999-01-01

    The present study investigated in vitro the regulatory effects of T helper 1 (Th1)-type (interferon-γ, IFN-γ; interleukin-12, IL-12) and Th2-type cytokines (IL-10, IL-13) on Onchocerca volvulus-specific cellular reactivity in onchocerciasis patients, and in exposed endemic control individuals presenting no clinical and parasitological signs of disease. In both patients and controls, addition of IL-10 dose-dependently depressed O. volvulus antigen (OvAg)-specific cellular proliferation, and peripheral blood mononuclear cells (PBMC) from patients who were more sensitive to the suppressive effect of IL-10 than those from endemic controls. However, neutralization of IL-10 by specific antibody did not reverse cellular hyporesponsiveness. In contrast to the inhibitory effects of IL-10, exogenous IL-12 and IL-13 augmented PBMC proliferative responses to OvAg both in patients and controls (P volvulus-specific cellular responsiveness in humans. PMID:10447735

  17. CD1d-dependent NKT cells play a protective role in acute and chronic arthritis models by ameliorating antigen-specific Th1 responses

    DEFF Research Database (Denmark)

    Teige, Anna; Bockermann, Robert; Hasan, Maruf

    2010-01-01

    arthritis in CIA was also worse in the absence of CD1d-dependent NKTs. Elevated levels of Ag-specific IFN-gamma production accompanied these findings rather than changes in IL-17alpha. Depletion of NK1.1(+) cells supported these findings in AIA and CIA. This report provides support for CD1d-dependent NKTs...

  18. Cyclopia Extracts Enhance Th1-, Th2-, and Th17-type T Cell Responses and Induce Foxp3+ Cells in Murine Cell Culture.

    Science.gov (United States)

    Murakami, Shiho; Miura, Yutaka; Hattori, Makoto; Matsuda, Hiroshi; Malherbe, Christiaan J; Muller, Christo J F; Joubert, Elizabeth; Yoshida, Tadashi

    2017-11-02

    Cyclopia genistoides, one of the traditional South African medicinal plants, and other species of the same genus offer noteworthy phenolic profiles, in particular high levels of the anti-allergic xanthone mangiferin. Hot water and 40% ethanol-water (v/v) extracts, prepared from C. genistoides, Cyclopia subternata, and Cyclopia maculata, were tested for immune-regulating activity in vitro using murine splenocytes and mesenteric lymph node cells. The 40% ethanol-water extracts of C. genistoides and C. subternata significantly enhanced production of several types of cytokines, including IL-4, IL-17, and IFN-γ, by antigen-stimulated splenocytes. A concentration-dependent response was observed, noticeably for IFN-γ production. The activity of the extracts did not correlate with the content of any of the major phenolic compounds, indicative that other extract constituents also play a role in immunomodulation. Additionally, the increased ratio of CD4(+)CD25(+)Foxp3(+) Treg cells to total CD4(+) cells indicated induction of Foxp3(+) cells when mesenteric lymph node cells were cultured in the presence of these two extracts. This study is the first reporting immunostimulatory activity for Cyclopia, which are widely consumed as the herbal tea known as honeybush, underpinning further investigations into the potential use of its extracts as adjuvants for mucosal immunotherapy. Georg Thieme Verlag KG Stuttgart · New York.

  19. Pegylation of DDA:TDB liposomal adjuvants reduces the vaccine depot effect and alters the Th1/Th2 immune responses.

    Science.gov (United States)

    Kaur, Randip; Bramwell, Vincent W; Kirby, Daniel J; Perrie, Yvonne

    2012-02-28

    The adjuvant efficacy of cationic liposomes composed of dimethyldioctadecylammonium bromide and trehalose dibehenate (DDA:TDB) is well established. Whilst the mechanism behind its immunostimulatory action is not fully understood, the ability of the formulation to promote a 'depot effect' is a consideration. The depot effect has been suggested to be primarily due to their cationic nature which results in electrostatic adsorption of the antigen and aggregation of the vesicles at the site of injection. The aim of the study was to further test this hypothesis by investigating whether sterically stabilising DDA:TDB with polyethylene glycol (PEG) reduces aggregation, and subsequently influences the formation of a depot at the site of injection. Results reported demonstrate that high (25%) levels of PEG was able to significantly inhibit the formation of a liposome depot and also severely limit the retention of antigen at the site, resulting in a faster drainage of the liposomes from the site of injection. This change in biodistribution profile was reflected in the immunisation response, where lower levels of IgG2b antibody and IFN-γ and higher level of IL-5 cytokine were found. Furthermore entrapping antigen within DDA:TDB liposomes did not improve antigen retention at the injection site compared surface adsorbed antigen. Copyright © 2011 Elsevier B.V. All rights reserved.

  20. Immunization with the DNA-encoding N-terminal domain of proteophosphoglycan of Leishmania donovani generates Th1-type immunoprotective response against experimental visceral leishmaniasis.

    Science.gov (United States)

    Samant, Mukesh; Gupta, Reema; Kumari, Shraddha; Misra, Pragya; Khare, Prashant; Kushawaha, Pramod Kumar; Sahasrabuddhe, Amogh Anant; Dube, Anuradha

    2009-07-01

    Leishmania produce several types of mucin-like glycoproteins called proteophosphoglycans (PPGs) which exist as secretory as well as surface-bound forms in both promastigotes and amastigotes. The structure and function of PPGs have been reported to be species and stage specific as in the case of Leishmania major and Leishmania mexicana; there has been no such information available for Leishmania donovani. We have recently demonstrated that PPG is differentially expressed in sodium stibogluconate-sensitive and -resistant clinical isolates of L. donovani. To further elucidate the structure and function of the ppg gene of L. donovani, a partial sequence of its N-terminal domain of 1.6 kb containing the majority of antigenic determinants, was successfully cloned and expressed in prokaryotic as well as mammalian cells. We further evaluated the DNA-encoding N-terminal domain of the ppg gene as a vaccine in golden hamsters (Mesocricetus auratus) against the L. donovani challenge. The prophylactic efficacy to the tune of approximately 80% was observed in vaccinated hamsters and all of them could survive beyond 6 mo after challenge. The efficacy was supported by a surge in inducible NO synthase, IFN-gamma, TNF-alpha, and IL-12 mRNA levels along with extreme down-regulation of TGF-beta, IL-4, and IL-10. A rise in the level of Leishmania-specific IgG2 was also observed which was indicative of enhanced cellular immune response. The results suggest the N-terminal domain of L. donovani ppg as a potential DNA vaccine against visceral leishmaniasis.

  1. Interleukin-12 augments a Th1-type immune response manifested as lymphocyte proliferation and interferon gamma production in Leishmania infantum-infected dogs.

    Science.gov (United States)

    Strauss-Ayali, Dalit; Baneth, Gad; Shor, Sharon; Okano, Fumiyoshi; Jaffe, Charles L

    2005-01-01

    The dog is the major reservoir for human visceral leishmaniasis caused by Leishmania infantum. Interleukin-12 is considered to have an essential role in the development of both innate and adaptive immunity to Leishmania spp. and other intracellular pathogens. This study focused on the influence of IL-12 in experimental and natural canine visceral leishmaniasis. Responses of peripheral blood mononuclear cells to IL-12, interleukin-10 and Leishmania soluble antigen were evaluated in L. infantum experimentally infected oligosymptomatic beagles, uninfected beagles, naturally infected polysymptomatic dogs, and their matched uninfected controls. Leishmania soluble antigen induced strong peripheral blood mononuclear cells proliferation both in experimentally infected dogs (median stimulation index [SI]=15.01), and in naturally infected dogs (SI=8.86), but not by cells from the control groups. IL-12 addition further enhanced cell proliferation in naturally (SI=14.95), but not in experimentally infected animals. Peripheral blood mononuclear cells from experimentally infected dogs were able to produce significant amounts of IFN-gamma (3.39 ng/ml) upon LSA stimulation, but no such production was detected in cells from naturally infected or control animals. Interestingly, addition of IL-12 reversed the inhibitory effect of LSA on IFN-gamma production by cells from polysymptomatic naturally infected dogs and the uninfected beagles (4.84 and 7.45 ng/ml, respectively), and further increased IFN-gamma production by peripheral blood mononuclear cells from experimentally infected oligosymptomatic dogs (29.28 ng/ml). IFN-gamma mRNA expression correlated well with IFN-gamma production. Addition of IL-10 to Leishmania soluble antigen stimulated peripheral blood mononuclear cells inhibited proliferation and IFN-gamma production in experimentally infected dogs. Thus, the ability of IL-12 to augment IFN-gamma production by peripheral blood mononuclear cells from dogs with experimental or

  2. Immunotherapeutic vitamin E nanoemulsion synergies the antiproliferative activity of paclitaxel in breast cancer cells via modulating Th1 and Th2 immune response.

    Science.gov (United States)

    Pawar, Vivek K; Panchal, Samir B; Singh, Yuvraj; Meher, Jaya Gopal; Sharma, Komal; Singh, Pankaj; Bora, Himangshu K; Singh, Akhilesh; Datta, Dipak; Chourasia, Manish K

    2014-12-28

    Paclitaxel (PTX) is used as first line treatment for metastatic breast cancer but the relief comes at a heavy cost in terms of accompanying adverse effects. The pharmaceutical credentials of PTX are further dampened by the intrinsically low aqueous solubility. In order to sideline such insidious tendencies, PTX was incorporated in a vitamin E nanoemulsion using high pressure homogenization. The encapsulation efficiency of PTX in nanoemulsion was 97.81±2.7% and a sustained drug release profile was obtained. PTX loaded nanoemulsion exhibited higher cytotoxicity in breast cancer cell line (MCF-7) when compared to free PTX and marketed formulation (Taxol). Cell cycle arrest study depicted that MCF-7 cells treated with PTX loaded nanoemulsion showed high arrest in G2-M phase. Moreover blank nanoemulsion induced additional apoptosis in breast cancer cells through G1-S arrest by disrupting mitochondrial membrane potential. Cytokine estimation study in macrophages showed that both PTX loaded nanoemulsion and blank nanoemulsion enhanced secretion of IL-12 and downregulated secretion of IL-4 and IL-10. Results suggest that inclusion of vitamin E in nanoemulsion opened multiple complementary molecular effects which not only magnified the principle antiproliferative activity of PTX but also independently showcased potential in restoring the proactive nature of the breast cancer slackened chronic immune response. In-vivo anticancer activity showed significantly improved efficacy of PTX loaded nanoemlsion compare to Taxol and free PTX. The list of plausible advantages of PTX nanoemulsification was further substantiated by acceptable haemolytic potential, reduced in-vivo toxicity and conveniently modified pharmacokinetic profile in which the AUC and MRT were extended considerably. Overall, there were strong evidences that developed formulation can serve as a viable alternative to currently available PTX options. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. TLR2 and TLR4 signaling pathways are required for recombinant Brucella abortus BCSP31-induced cytokine production, functional upregulation of mouse macrophages, and the Th1 immune response in vivo and in vitro.

    Science.gov (United States)

    Li, Jia-Yun; Liu, Yuan; Gao, Xiao-Xue; Gao, Xiang; Cai, Hong

    2014-09-01

    Brucella abortus is a zoonotic Gram-negative pathogen that causes brucelosis in ruminants and humans. Toll-like receptors (TLRs) recognize Brucella abortus and initiate antigen-presenting cell activities that affect both innate and adaptive immunity. In this study, we focused on recombinant Brucella cell-surface protein 31 (rBCSP31) to determine its effects on mouse macrophages. Our results demonstrated that rBCSP31 induced TNF-α, IL-6 and IL-12p40 production, which depended on the activation of mitogen-activated protein kinases (MAPKs) by stimulating the rapid phosphorylation of p38 and JNK and the activation of transcription factor NF-κB in macrophages. In addition, continuous exposure (>24 h) of RAW264.7 cells to rBCSP31 significantly enhanced IFN-γ-induced expression of MHC-II and the ability to present rBCSP31 peptide to CD4(+) T cells. Furthermore, we found that rBCSP31 could interact with both TLR2 and TLR4. The rBCSP31-induced cytokine production by macrophages from TLR2(-/-) and TLR4(-/-) mice was lower than that from C57BL/6 macrophages, and the activation of NF-κB and MAPKs was attenuated in macrophages from TLR2(-/-) and TLR4(-/-) mice. In addition, CD4(+) T cells from C57BL/6 mice immunized with rBCSP31 produced higher levels of IFN-γ and IL-2 compared with CD4(+) T cells from TLR2(-/-) and TLR4(-/-) mice. Macrophages from immunized C57BL/6 mice produced higher levels of IL-12p40 than those from TLR2(-/-) and TLR4(-/-) mice. Furthermore, immunization with rBCSP31 provided better protection in C57BL/6 mice than in TLR2(-/-) and TLR4(-/-) mice after B. abortus 2308 challenge. These results indicate that rBCSP31 is a TLR2 and TLR4 agonist that induces cytokine production, upregulates macrophage function and induces the Th1 immune response.

  4. Antigen experience shapes phenotype and function of memory Th1 cells.

    Directory of Open Access Journals (Sweden)

    Aaruni Khanolkar

    Full Text Available Primary and secondary (boosted memory CD8 T cells exhibit differences in gene expression, phenotype and function. The impact of repeated antigen stimulations on memory CD4 T cells is largely unknown. To address this issue, we utilized LCMV and Listeria monocytogenes infection of mice to characterize primary and secondary antigen (Ag-specific Th1 CD4 T cell responses. Ag-specific primary memory CD4 T cells display a CD62L(loCCR7(hi CD27(hi CD127(hi phenotype and are polyfunctional (most produce IFNγ, TNFα and IL-2. Following homologous prime-boost immunization we observed pathogen-specific differences in the rate of CD62L and CCR7 upregulation on memory CD4 T cells as well as in IL-2+IFNγco-production by secondary effectors. Phenotypic and functional plasticity of memory Th1 cells was observed following heterologous prime-boost immunization, wherein secondary memory CD4 T cells acquired phenotypic and functional characteristics dictated by the boosting agent rather than the primary immunizing agent. Our data also demonstrate that secondary memory Th1 cells accelerated neutralizing Ab formation in response to LCMV infection, suggesting enhanced capacity of this population to provide quality help for antibody production. Collectively these data have important implications for prime-boost vaccination strategies that seek to enhance protective immune responses mediated by Th1 CD4 T cell responses.

  5. The TLR4 Agonist Vaccine Adjuvant, GLA-SE, Requires Canonical and Atypical Mechanisms of Action for TH1 Induction.

    Directory of Open Access Journals (Sweden)

    Natasha Dubois Cauwelaert

    Full Text Available The Toll-like receptor 4 agonist glucopyranosyl lipid adjuvant formulated in a stable emulsion (GLA-SE promotes strong TH1 and balanced IgG1/IgG2 responses to protein vaccine antigens. This enhanced immunity is sufficient to provide protection against many diseases including tuberculosis and leishmaniasis. To better characterize the adjuvant action it is important to understand how the different cytokines and transcription factors contribute to the initiation of immunity. In the present study using T-bet-/- and IL-12-/- mice and a blocking anti-IFNαR1 monoclonal antibody, we define mechanisms of adjuvant activity of GLA-SE. In accordance with previous studies of TLR4 agonist based adjuvants, we found that TH1 induction via GLA-SE was completely dependent upon T-bet, a key transcription factor for IFNγ production and TH1 differentiation. Consistent with this, deficiency of IL-12, a cytokine canonical to TH1 induction, ablated TH1 induction via GLA-SE. Finally we demonstrate that the innate immune response to GLA-SE, including rapid IFNγ production by memory CD8+ T cells and NK cells, was contingent on type I interferon, a cytokine group whose association with TH1 induction is contextual, and that they contributed to the adjuvant activity of GLA-SE.

  6. Honeybee (Apis mellifera Venom Reinforces Viral Clearance during the Early Stage of Infection with Porcine Reproductive and Respiratory Syndrome Virus through the Up-Regulation of Th1-Specific Immune Responses

    Directory of Open Access Journals (Sweden)

    Jin-A Lee

    2015-05-01

    Full Text Available Porcine reproductive and respiratory syndrome (PRRS is a chronic and immunosuppressive viral disease that is responsible for substantial economic losses for the swine industry. Honeybee venom (HBV is known to possess several beneficial biological properties, particularly, immunomodulatory effects. Therefore, this study aimed at evaluating the effects of HBV on the immune response and viral clearance during the early stage of infection with porcine reproductive and respiratory syndrome virus (PRRSV in pigs. HBV was administered via three routes of nasal, neck, and rectal and then the pigs were inoculated with PRRSV intranasally. The CD4+/CD8+ cell ratio and levels of interferon (IFN-γ and interleukin (IL-12 were significantly increased in the HBV-administered healthy pigs via nasal and rectal administration. In experimentally PRRSV-challenged pigs with virus, the viral genome load in the serum, lung, bronchial lymph nodes and tonsil was significantly decreased, as was the severity of interstitial pneumonia, in the nasal and rectal administration group. Furthermore, the levels of Th1 cytokines (IFN-γ and IL-12 were significantly increased, along with up-regulation of pro-inflammatory cytokines (TNF-α and IL-1β with HBV administration. Thus, HBV administration—especially via the nasal or rectal route—could be a suitable strategy for immune enhancement and prevention of PRRSV infection in pigs.

  7. Anti-CD20 therapy induces a memory Th1 response through the IFN-γ/IL-12 axis and prevents protumor regulatory T-cell expansion in mice.

    Science.gov (United States)

    Deligne, C; Metidji, A; Fridman, W-H; Teillaud, J-L

    2015-04-01

    The long-lasting clinical response by lymphoma patients to anti-CD20 therapy has been attributed to the induction of an anti-tumor adaptive immunity. We previously demonstrated that a CD4-dependent mechanism is responsible for the long-term protection of CD20(+) tumor-bearing mice by anti-CD20 treatment. Here, we compare tumor immunity in tumor-bearing animals that did or did not receive anti-CD20 treatment. Splenic CD4(+)FoxP3(+) regulatory T cells (Tregs) expanded substantially in untreated mice that exhibited then a reduced survival, whereas Tregs depletion led to long-term survival of the animals, suggesting the establishment of a Treg-dependent immunosuppressive environment after tumor injection. Strikingly, anti-CD20 therapy reversed the initial expansion of Tregs, and was accompanied by a marked increase in the number of Th1 cells, with no detectable change in Th2 and Th17 cell numbers. Interleukin-12 serum level was also increased by the anti-CD20 treatment, and activated myeloid dendritic cells producing interleukin-12 could be detected in lymph nodes of treated animals, while interferon-γ blockade strongly reduced survival. Also, CD4(+) effector memory T cells were evidenced in surviving animals, and the transfer of CD4(+) T cells induced long-term protection. Thus, anti-CD20 therapy promotes strong anti-tumor adaptive immunity, opposes Treg expansion and inhibits tumor cells from maintaining an immunosuppressive environment.

  8. Keratinocytes determine Th1 immunity during early experimental leishmaniasis.

    Directory of Open Access Journals (Sweden)

    Jan M Ehrchen

    2010-04-01

    Full Text Available Experimental leishmaniasis is an excellent model system for analyzing Th1/Th2 differentiation. Resistance to Leishmania (L. major depends on the development of a L. major specific Th1 response, while Th2 differentiation results in susceptibility. There is growing evidence that the microenvironment of the early affected tissue delivers the initial triggers for Th-cell differentiation. To analyze this we studied differential gene expression in infected skin of resistant and susceptible mice 16h after parasite inoculation. Employing microarray technology, bioinformatics, laser-microdissection and in-situ-hybridization we found that the epidermis was the major source of immunomodulatory mediators. This epidermal gene induction was significantly stronger in resistant mice especially for several genes known to promote Th1 differentiation (IL-12, IL-1beta, osteopontin, IL-4 and for IL-6. Expression of these cytokines was temporally restricted to the crucial time of Th1/2 differentiation. Moreover, we revealed a stronger epidermal up-regulation of IL-6 in the epidermis of resistant mice. Accordingly, early local neutralization of IL-4 in resistant mice resulted in a Th2 switch and mice with a selective IL-6 deficiency in non-hematopoietic cells showed a Th2 switch and dramatic deterioration of disease. Thus, our data indicate for the first time that epidermal cytokine expression is a decisive factor in the generation of protective Th1 immunity and contributes to the outcome of infection with this important human pathogen.

  9. Immunomodulatory effect of tea saponin in immune T-cells and T-lymphoma cells via regulation of Th1, Th2 immune response and MAPK/ERK2 signaling pathway.

    Science.gov (United States)

    Bhardwaj, Jyoti; Chaudhary, Narendra; Seo, Hyo-Jin; Kim, Min-Yong; Shin, Tai-Sun; Kim, Jong-Deog

    2014-06-01

    The anti-cancer activity of saponins and phenolic compounds present in green tea was previously reported. However, the immunomodulatory and adjuvanticity activity of tea saponin has never been studied. In this study, we investigated the immunomodulatory effect of tea saponin in T-lymphocytes and EL4 cells via regulation of cytokine response and mitogen-activated protein kinases (MAPK) signaling pathway. Quantitative analysis of mRNA expression level of cytokines were performed by reverse transcription polymerase chain reaction following stimulation with tea saponin, ovalbumin (OVA) alone or tea saponin in combination with OVA. Tea saponin inhibited the proliferation of EL4 cells measured in a dose-dependent manner. No cytotoxicity effect of tea saponin was detected in T-lymphocytes; rather, tea saponin enhanced the proliferation of T-lymphocytes. Tea saponin with OVA increased the expression of interleukin (IL)-1, IL-2, IL-12, interferon-γ and tumor necrosis factor (TNF)-α and decreased the expression level of IL-10 and IL-8 in T-lymphocytes. Furthermore, tea saponin, in the presence of OVA, downregulated the MAPK signaling pathway via inhibition of IL-4, IL-8 and nuclear factor kappaB (NF-κB) in EL4 cells. Th1 cytokines enhancer and Th2 cytokines and NF-κB inhibitor, tea saponin can markedly inhibit the proliferation and invasiveness of T-lymphoma (EL4) cells, possibly due to TNF-α- and NF-κB-mediated regulation of MAPK signaling pathway.

  10. Advax4 delta inulin combination adjuvant together with ECMX, a fusion construct of four protective mTB antigens, induces a potent Th1 immune response and protects mice against Mycobacterium tuberculosis infection.

    Science.gov (United States)

    de Paula Oliveira Santos, Bruno; Trentini, Monalisa Martins; Machado, Renato Beilner; Rúbia Nunes Celes, Mara; Kipnis, André; Petrovsky, Nikolai; Junqueira-Kipnis, Ana Paula

    2017-12-02

    Tuberculosis (TB) remains a main public health concern and 10.4 million new cases occurred in 2015 around the world. BCG is the only approved vaccine against TB, but has variable efficacy and new vaccines are needed. We developed two new mTB vaccine candidates based on the recombinant fusion proteins, rCMX and rECMX formulated with Advax4, a new combination adjuvant combining delta inulin, CpG oligonucleotide and murabutide. BALB/c mice were immunized three times intramuscularly with these vaccine formulations. Injection of Advax4 alone increased the percentage of lymphatic endothelial cells and activated macrophages (F480/CD11b+) in the draining lymph nodes consistent with a chemotactic adjuvant effect. Advax4+CMX and Advax4+ECMX induced the highest levels of IgG1 and IgG2a antibodies against rCMX and rECMX, respectively. Immunized mice challenged with Mycobacterium tuberculosis (Mtb) had increased vaccine-specific Th1 responses in the lungs together with reduced Mtb - associated alveolar damage, although only the Advax4+ECMX vaccine demonstrated significant reduction of lung bacterial load. This study confirmed Advax4+ECMX as a potential TB vaccine candidate, with potential for further optimization and clinical development.

  11. Development of a nasal vaccine for chronic hepatitis B infection that uses the ability of hepatitis B core antigen to stimulate a strong Th1 response against hepatitis B surface antigen.

    Science.gov (United States)

    Aguilar, J C; Lobaina, Y; Muzio, V; García, D; Pentón, E; Iglesias, E; Pichardo, D; Urquiza, D; Rodríguez, D; Silva, D; Petrovsky, N; Guillén, G

    2004-10-01

    There are estimated to be 350 million chronic carriers of hepatitis B infection worldwide. Patients with chronic hepatitis B are at risk of liver cirrhosis with associated mortality because of hepatocellular carcinoma and other complications. An important goal, therefore, is the development of an effective therapeutic vaccine against chronic hepatitis B virus (HBV). A major barrier to the development of such a vaccine is the impaired immune response to HBV antigens observed in the T cells of affected patients. One strategy to overcome these barriers is to activate mucosal T cells through the use of nasal vaccination because this may overcome the systemic immune downregulation that results from HBV infection. In addition, it may be beneficial to present additional HBV epitopes beyond those contained in the traditional hepatitis B surface antigen (HbsAg) vaccine, for example, by using the hepatitis B core antigen (HBcAg). This is advantageous because HBcAg has a unique ability to act as a potent Th1 adjuvant to HbsAg, while also serving as an immunogenic target. In this study we describe the effect of coadministration of HBsAg and HBcAg as part of a strategy to develop a more potent and effective HBV therapeutic vaccine. Copyright 2004 Australasian Society for Immunology Inc.

  12. F1 Domain of theLeishmania (Leishmania) donovaniNucleoside Hydrolase Promotes a Th1 Response inLeishmania (Leishmania) infantumCured Patients and in Asymptomatic Individuals Living in an Endemic Area of Leishmaniasis.

    Science.gov (United States)

    Carrillo, Eugenia; Fernandez, Laura; Ibarra-Meneses, Ana Victoria; Santos, Micheli L B; Nico, Dirlei; de Luca, Paula M; Correa, Cristiane Bani; de Almeida, Roque Pacheco; Moreno, Javier; Palatnik-de-Sousa, Clarisa B

    2017-01-01

    The Leishmania (Leishmania) donovani nucleoside hydrolase NH36 is the main antigen of the Leishmune ® vaccine and one of the promising candidates for vaccination against visceral leishmaniasis. The antigenicity of the N-terminal (F1), the central (F2), or the C-terminal recombinant domain (F3) of NH36 was evaluated using peripheral blood mononuclear cells (PBMC) from individuals infected with L. (L.) infantum from an endemic area of visceral leishmaniasis of Spain. Both NH36 and F1 domains significantly increased the PBMC proliferation stimulation index of cured patients and infected asymptomatic individuals compared to healthy controls. Moreover, F1 induced a 19% higher proliferative response than NH36 in asymptomatic exposed subjects. In addition, in patients cured from visceral leishmaniasis, proliferation in response to NH36 and F1 was accompanied by a significant increase of IFN-γ and TNF-α secretion, which was 42-43% higher, in response to F1 than to NH36. The interleukin 17 (IL-17) secretion was stronger in asymptomatic subjects, in response to F1, as well as in cured cutaneous leishmaniasis after NH36 stimulation. While no IL-10 secretion was determined by F1, a granzyme B increase was detected in supernatants from cured patients after stimulation with either NH36 or F1. These data demonstrate that F1 is the domain of NH36 that induces a recall cellular response in individuals with acquired resistance to the infection by L. (L.) infantum . In addition, F1 and NH36 discriminated the IgG3 humoral response in patients with active visceral leishmaniasis due to L. (L.) donovani (Ethiopia) and L. (L.) infantum (Spain) from that of endemic and non-endemic area controls. NH36 showed higher reactivity with sera from L. (L.) donovani -infected individuals, indicating species specificity. We conclude that the F1 domain, previously characterized as an inducer of the Th1 and Th17 responses in cured/exposed patients infected with L. (L.) infantum chagasi , may also be

  13. F1 Domain of the Leishmania (Leishmania) donovani Nucleoside Hydrolase Promotes a Th1 Response in Leishmania (Leishmania) infantum Cured Patients and in Asymptomatic Individuals Living in an Endemic Area of Leishmaniasis

    Science.gov (United States)

    Carrillo, Eugenia; Fernandez, Laura; Ibarra-Meneses, Ana Victoria; Santos, Micheli L. B.; Nico, Dirlei; de Luca, Paula M.; Correa, Cristiane Bani; de Almeida, Roque Pacheco; Moreno, Javier; Palatnik-de-Sousa, Clarisa B.

    2017-01-01

    The Leishmania (Leishmania) donovani nucleoside hydrolase NH36 is the main antigen of the Leishmune® vaccine and one of the promising candidates for vaccination against visceral leishmaniasis. The antigenicity of the N-terminal (F1), the central (F2), or the C-terminal recombinant domain (F3) of NH36 was evaluated using peripheral blood mononuclear cells (PBMC) from individuals infected with L. (L.) infantum from an endemic area of visceral leishmaniasis of Spain. Both NH36 and F1 domains significantly increased the PBMC proliferation stimulation index of cured patients and infected asymptomatic individuals compared to healthy controls. Moreover, F1 induced a 19% higher proliferative response than NH36 in asymptomatic exposed subjects. In addition, in patients cured from visceral leishmaniasis, proliferation in response to NH36 and F1 was accompanied by a significant increase of IFN-γ and TNF-α secretion, which was 42–43% higher, in response to F1 than to NH36. The interleukin 17 (IL-17) secretion was stronger in asymptomatic subjects, in response to F1, as well as in cured cutaneous leishmaniasis after NH36 stimulation. While no IL-10 secretion was determined by F1, a granzyme B increase was detected in supernatants from cured patients after stimulation with either NH36 or F1. These data demonstrate that F1 is the domain of NH36 that induces a recall cellular response in individuals with acquired resistance to the infection by L. (L.) infantum. In addition, F1 and NH36 discriminated the IgG3 humoral response in patients with active visceral leishmaniasis due to L. (L.) donovani (Ethiopia) and L. (L.) infantum (Spain) from that of endemic and non-endemic area controls. NH36 showed higher reactivity with sera from L. (L.) donovani-infected individuals, indicating species specificity. We conclude that the F1 domain, previously characterized as an inducer of the Th1 and Th17 responses in cured/exposed patients infected with L. (L.) infantum chagasi, may also be

  14. F1 Domain of the Leishmania (Leishmania donovani Nucleoside Hydrolase Promotes a Th1 Response in Leishmania (Leishmania infantum Cured Patients and in Asymptomatic Individuals Living in an Endemic Area of Leishmaniasis

    Directory of Open Access Journals (Sweden)

    Eugenia Carrillo

    2017-07-01

    Full Text Available The Leishmania (Leishmania donovani nucleoside hydrolase NH36 is the main antigen of the Leishmune® vaccine and one of the promising candidates for vaccination against visceral leishmaniasis. The antigenicity of the N-terminal (F1, the central (F2, or the C-terminal recombinant domain (F3 of NH36 was evaluated using peripheral blood mononuclear cells (PBMC from individuals infected with L. (L. infantum from an endemic area of visceral leishmaniasis of Spain. Both NH36 and F1 domains significantly increased the PBMC proliferation stimulation index of cured patients and infected asymptomatic individuals compared to healthy controls. Moreover, F1 induced a 19% higher proliferative response than NH36 in asymptomatic exposed subjects. In addition, in patients cured from visceral leishmaniasis, proliferation in response to NH36 and F1 was accompanied by a significant increase of IFN-γ and TNF-α secretion, which was 42–43% higher, in response to F1 than to NH36. The interleukin 17 (IL-17 secretion was stronger in asymptomatic subjects, in response to F1, as well as in cured cutaneous leishmaniasis after NH36 stimulation. While no IL-10 secretion was determined by F1, a granzyme B increase was detected in supernatants from cured patients after stimulation with either NH36 or F1. These data demonstrate that F1 is the domain of NH36 that induces a recall cellular response in individuals with acquired resistance to the infection by L. (L. infantum. In addition, F1 and NH36 discriminated the IgG3 humoral response in patients with active visceral leishmaniasis due to L. (L. donovani (Ethiopia and L. (L. infantum (Spain from that of endemic and non-endemic area controls. NH36 showed higher reactivity with sera from L. (L. donovani-infected individuals, indicating species specificity. We conclude that the F1 domain, previously characterized as an inducer of the Th1 and Th17 responses in cured/exposed patients infected with L. (L. infantum chagasi, may

  15. Lipophilic fractions from the marine sponge Halichondria sitiens decrease secretion of pro-inflammatory cytokines by dendritic cells and decrease their ability to induce a Th1 type response by allogeneic CD4+ T cells.

    Science.gov (United States)

    Di, Xiaxia; Oskarsson, Jon T; Omarsdottir, Sesselja; Freysdottir, Jona; Hardardottir, Ingibjorg

    2017-12-01

    Halichondria (Halichondriidae) marine sponges contain components possessing various biological activities, but immunomodulation is not among the ones reported. This study evaluated the immunomodulatory effects of fractions/compounds from Halichondria sitiens Schmidt. Crude dichloromethane/methanol extracts of H. sitiens were subjected to various chromatographic techniques to obtain fractions/compounds with immunomodulatory activity, using bioassay-guided isolation. The effects of the fractions/compounds were determined by measuring secretion of cytokines and expression of surface molecules by dendritic cells (DCs) and their ability to stimulate and modify cytokine secretion by allogeneic CD4+ T cells. The bioactive fractions were chemically analyzed to identify the immunomodulatory constituents by 1D, 2D NMR, and HRMS data. Several lipophilic fractions from H. sitiens at 10 μg/mL decreased secretion of the pro-inflammatory cytokines IL-12p40 and IL-6 by the DCs, with maximum inhibition being 64% and 25%, respectively. In addition, fractions B3b3F and B3b3J decreased the ability of DCs to induce T cell secretion of IFN-γ. Fraction B3b3 induced morphological changes in DCs, characterized by extreme elongation of dendrites and cell clustering. Chemical screening revealed the presence of glycerides and some minor unknown constituents in the biologically active fractions. One new glyceride, 2,3-dihydroxypropyl 2-methylhexadecanoate (1), was isolated from one fraction and two known compounds, 3-[(1-methoxyhexadecyl)oxy]propane-1,2-diol (2) and monoheptadecanoin (3), were identified in another, but none of them had immunomodulatory activity. These results demonstrate that several lipophilic fractions from H. sitiens have anti-inflammatory effects on DCs and decrease their ability to induce a Th1 type immune response.

  16. Th1 Th2, Tc1 Tc2 cells of patients with otolaryngological diseases

    Directory of Open Access Journals (Sweden)

    Nobuo Ohta

    2004-01-01

    Full Text Available Cytokines are important regulatory mediators secreted by T cells and other immunoactive cells. Based on the cytokine synthesis patterns, CD4 T cells can often be classified into at least two populations with different immune regulatory functions. The Th1 cells, producing interleukin (IL-2 and interferon (IFN-γ, are often associated with cell-mediated immune responses such as delayed type hypersensitivity (DTH, whereas Th2 cells, secreting IL-4, IL-5 and IL-13, usually provide B cell help and enhance allergic reactions. Naïve CD8 T cells, similar to CD4 T cells, can differentiate into at least two subsets of cytolytic effector cells with distinct cytokine patterns. The Tc1 cells secrete a Th 1 - like cytokine pattern, including IL-2 and IFN-γ. The Tc2 cells produce Th2 cytokines, including IL-4, IL-5 and 11—10. There is increasing evidence that Th1/Th2 and Tc1/Tc2 cytokine imbalance has been of patho- genetic importance in various diseases, such as allergic and autoimmune diseases. The present review article focuses on the evidence that the imbalance of Th1/Th2 and Tc1/Tc2 cytokines plays an important role in various otolaryngological diseases, such as Kimura's disease, Wegener's granulomatosism, acute perceptive hearing loss and Meniere's disease. It is concluded that the predominance of Th 1 or Th2 and Tc1 or Tc2 cells may contribute to the mechanism in the pathogenesis of these otolaryngological diseases.

  17. Human Rhinovirus Proteinase 2A Induces Th1 and Th2 Immunity in COPD

    Science.gov (United States)

    Singh, Manisha; Lee, Seung-Hyo; Porter, Paul; Xu, Chuang; Ohno, Ayako; Atmar, Robert L.; Greenberg, Stephen B.; Bandi, Venkata; Gern, Jim; Amineva, Svetlana; Aminev, Alex; Skern, Tim; Smithwick, Pamela; Perusich, Sarah; Barrow, Nadia; Roberts, Luz; Corry, David B.; Kheradmand, Farrah

    2010-01-01

    Background Tobacco related lung diseases including chronic obstructive pulmonary disease (COPD), are major causes of lung-related disability and death worldwide. Acute exacerbation of COPD (AE-COPD) is commonly associated with upper and lower respiratory viral infections and may result in respiratory failure in those with advanced lung disease. Objective We sought to determine the mechanism underlying COPD exacerbation, and host response to pathogen-derived factors. Methods Over a 24 months period, we assessed the viral causes for upper and lower respiratory infections in COPD (n=155) and control (n=103) subjects. We collected nasal and bronchoalveolar lavage (BAL) fluid and peripheral blood under baseline and exacerbated condition. We determined the effect of human rhinovirus (HRV) proteinases on T cell activation in humans, and in mice. Results HRVs are isolated from nasal and lung fluid from subjects with AE-COPD. BAL fluid, and CD4 T cells from COPD patients exhibited a type 1 T helper (Th1), and Th2 cell cytokine phenotype during acute infection. HRV-encoded proteinase 2A activated monocyte-derived dendritic cells in vitro, and induced strong Th1, and Th2 immune responses from CD4 T cells. Intranasal administration of recombinant rhinovirus proteinase 2A in mice resulted in an increase in airway hyperreactivity, lung inflammation, and IL-4 and IFN-γ production from CD4 T cells. Conclusion Our findings suggest that patients with severe COPD show Th1 and Th2 bias responses during AE-COPD. HRV-encoded proteinase 2A, like other microbial proteinases, could provide a Th1 and Th2-biasing adjuvant factor during upper and lower respiratory infection in patients with severe COPD. Alteration of the immune response to secreted viral proteinases may contribute to worsening of dyspnea and respiratory failure in COPD. PMID:20430426

  18. Dectin-1 isoforms contribute to distinct Th1/Th17 cell activation in mucosal candidiasis

    Science.gov (United States)

    Carvalho, Agostinho; Giovannini, Gloria; De Luca, Antonella; D'Angelo, Carmen; Casagrande, Andrea; Iannitti, Rossana G; Ricci, Giovanni; Cunha, Cristina; Romani, Luigina

    2012-01-01

    The recognition of β-glucans by dectin-1 has been shown to mediate cell activation, cytokine production and a variety of antifungal responses. Here, we report that the functional activity of dectin-1 in mucosal immunity to Candida albicans is influenced by the genetic background of the host. Dectin-1 was required for the proper control of gastrointestinal and vaginal candidiasis in C57BL/6, but not BALB/c mice; in fact, the latter showed increased resistance in the absence of dectin-1. The susceptibility of dectin-1-deficient C57BL/6 mice to infection was associated with defects in IL-17A and aryl hydrocarbon receptor-dependent IL-22 production and in adaptive Th1 responses. In contrast, the resistance of dectin-1-deficient BALB/c mice was associated with increased IL-17A and IL-22 production and the skewing towards Th1/Treg immune responses that provide immunological memory. Disparate canonical/noncanonical NF-κB signaling pathways downstream of dectin-1 were activated in the two different mouse strains. Thus, the net activity of dectin-1 in antifungal mucosal immunity is dependent on the host's genetic background, which affects both the innate cytokine production and the adaptive Th1/Th17 cell activation upon dectin-1 signaling. PMID:22543832

  19. Th1 and Th2 help for B cells

    DEFF Research Database (Denmark)

    Poudrier, J; Owens, T

    1995-01-01

    Sustained interaction with Th1 cells has been shown to induce IL-2 responsiveness by murine B cells. This is equivalently dependent on CD40, CD54/ICAM-1 and MHC II ligation, and co-cross-linking of CD54 and MHC II in the presence of IL-5 up-regulates a functional IL-2R on B cells. We now show...... that IL-5 (125 U/ml) synergizes with Th1 cells to induce B cell responses to IL-2, that are maintained following T-cell removal, e.g. autonomous. Th1 help in the absence of IL-5 resulted in weak or undetectable responses following T cell removal. The mechanism of IL-5 synergy involved persistence of IL-2R...... beta expression following T cell removal, as opposed to enhancement of IL-2R induction or function. The level of contact-induced IL-2R expression on B cells was not itself modified by IL-5. The effects of IL-5 did not overcome the requirement for T contact signals and treatment of B cells with soluble...

  20. What about Th1/Th2 in cutaneous leishmaniasis vaccine discovery?

    Directory of Open Access Journals (Sweden)

    Campos-Neto A.

    2005-01-01

    Full Text Available The T helper cell type 1 (Th1 response is essential to resist leishmaniasis, whereas the Th2 response favors the disease. However, many leishmanial antigens, which stimulate a Th1 immune response during the disease or even after the disease is cured, have been shown to have no protective action. Paradoxically, antigens associated with an early Th2 response have been found to be highly protective if the Th1 response to them is generated before infection. Therefore, finding disease-associated Th2 antigens and inducing a Th1 immune response to them using defined vaccination protocols is an interesting unorthodox alternative approach to the discovery of a leishmania vaccine.

  1. IL-4 attenuates Th1-associated chemokine expression and Th1 trafficking to inflamed tissues and limits pathogen clearance.

    Directory of Open Access Journals (Sweden)

    Christopher A Lazarski

    Full Text Available Interleukin 4 (IL-4 plays a central role in the orchestration of Type 2 immunity. During T cell activation in the lymph node, IL-4 promotes Th2 differentiation and inhibits Th1 generation. In the inflamed tissue, IL-4 signals promote innate and adaptive Type-2 immune recruitment and effector function, positively amplifying the local Th2 response. In this study, we identify an additional negative regulatory role for IL-4 in limiting the recruitment of Th1 cells to inflamed tissues. To test IL-4 effects on inflammation subsequent to Th2 differentiation, we transiently blocked IL-4 during ongoing dermal inflammation (using anti-IL-4 mAb and analyzed changes in gene expression. Neutralization of IL-4 led to the upregulation of a number of genes linked to Th1 trafficking, including CXCR3 chemokines, CCL5 and CCR5 and an associated increase in IFNγ, Tbet and TNFα genes. These gene expression changes correlated with increased numbers of IFNγ-producing CD4+ T cells in the inflamed dermis. Moreover, using an adoptive transfer approach to directly test the role of IL-4 in T cell trafficking to the inflamed tissues, we found IL-4 neutralization led to an early increase in Th1 cell recruitment to the inflamed dermis. These data support a model whereby IL-4 dampens Th1-chemokines at the site of inflammation limiting Th1 recruitment. To determine biological significance, we infected mice with Leishmania major, as pathogen clearance is highly dependent on IFNγ-producing CD4+ T cells at the infection site. Short-term IL-4 blockade in established L. major infection led to a significant increase in the number of IFNγ-producing CD4+ T cells in the infected ear dermis, with no change in the draining LN. Increased lymphocyte influx into the infected tissue correlated with a significant decrease in parasite number. Thus, independent of IL-4's role in the generation of immune effectors, IL-4 attenuates lymphocyte recruitment to the inflamed/infected dermis and

  2. IL-4 attenuates Th1-associated chemokine expression and Th1 trafficking to inflamed tissues and limits pathogen clearance.

    Science.gov (United States)

    Lazarski, Christopher A; Ford, Jill; Katzman, Shoshana D; Rosenberg, Alexander F; Fowell, Deborah J

    2013-01-01

    Interleukin 4 (IL-4) plays a central role in the orchestration of Type 2 immunity. During T cell activation in the lymph node, IL-4 promotes Th2 differentiation and inhibits Th1 generation. In the inflamed tissue, IL-4 signals promote innate and adaptive Type-2 immune recruitment and effector function, positively amplifying the local Th2 response. In this study, we identify an additional negative regulatory role for IL-4 in limiting the recruitment of Th1 cells to inflamed tissues. To test IL-4 effects on inflammation subsequent to Th2 differentiation, we transiently blocked IL-4 during ongoing dermal inflammation (using anti-IL-4 mAb) and analyzed changes in gene expression. Neutralization of IL-4 led to the upregulation of a number of genes linked to Th1 trafficking, including CXCR3 chemokines, CCL5 and CCR5 and an associated increase in IFNγ, Tbet and TNFα genes. These gene expression changes correlated with increased numbers of IFNγ-producing CD4+ T cells in the inflamed dermis. Moreover, using an adoptive transfer approach to directly test the role of IL-4 in T cell trafficking to the inflamed tissues, we found IL-4 neutralization led to an early increase in Th1 cell recruitment to the inflamed dermis. These data support a model whereby IL-4 dampens Th1-chemokines at the site of inflammation limiting Th1 recruitment. To determine biological significance, we infected mice with Leishmania major, as pathogen clearance is highly dependent on IFNγ-producing CD4+ T cells at the infection site. Short-term IL-4 blockade in established L. major infection led to a significant increase in the number of IFNγ-producing CD4+ T cells in the infected ear dermis, with no change in the draining LN. Increased lymphocyte influx into the infected tissue correlated with a significant decrease in parasite number. Thus, independent of IL-4's role in the generation of immune effectors, IL-4 attenuates lymphocyte recruitment to the inflamed/infected dermis and limits pathogen

  3. Restoration of innate immune activation accelerates Th1-cell priming and protection following pulmonary mycobacterial infection.

    Science.gov (United States)

    Lai, Rocky; Jeyanathan, Mangalakumari; Shaler, Christopher R; Damjanovic, Daniela; Khera, Amandeep; Horvath, Carly; Ashkar, Ali A; Xing, Zhou

    2014-05-01

    The immune mechanisms underlying delayed induction of Th1-type immunity in the lungs following pulmonary mycobacterial infection remain poorly understood. We have herein investigated the underlying immune mechanisms for such delayed responses and whether a selected innate immune-modulating strategy can accelerate Th1-type responses. We have found that, in the early stage of pulmonary infection with attenuated Mycobacterium tuberculosis (M.tb H37Ra), the levels of infection in the lung continue to increase logarithmically until days 14 and 21 postinfection in C57BL/6 mice. The activation of innate immune responses, particularly DCs, in the lung is delayed. This results in a delay in the subsequent downstream immune responses including the migration of antigen-bearing DCs to the draining lymph node (dLN), the Th1-cell priming in dLN, and the recruitment of Th1 cells to the lung. However, single lung mucosal exposure to the TLR agonist FimH postinfection is able to accelerate protective Th1-type immunity via facilitating DC migration to the lung and draining lymph nodes, enhancing DC antigen presentation and Th1-cell priming. These findings hold implications for the development of immunotherapeutic and vaccination strategies and suggest that enhancement of early innate immune activation is a viable option for improving Th1-type immunity against pulmonary mycobacterial diseases. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection.

    LENUS (Irish Health Repository)

    Brown, Aisling F

    2015-01-01

    Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans.

  5. Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection.

    Directory of Open Access Journals (Sweden)

    Aisling F Brown

    Full Text Available Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI. These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans.

  6. Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection

    Science.gov (United States)

    Lalor, Stephen J.; Leech, John M.; O’Keeffe, Kate M.; Mac Aogáin, Micheál; O’Halloran, Dara P.; Lacey, Keenan A.; Tavakol, Mehri; Hearnden, Claire H.; Fitzgerald-Hughes, Deirdre; Humphreys, Hilary; Fennell, Jérôme P.; van Wamel, Willem J.; Foster, Timothy J.; Geoghegan, Joan A.; Lavelle, Ed C.; Rogers, Thomas R.; McLoughlin, Rachel M.

    2015-01-01

    Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans. PMID:26539822

  7. Modelo natural de dicotomía TH1-TH2: La enfermedad de Hansen Th1-TH2 balance. Natural model: Hansen'disease

    Directory of Open Access Journals (Sweden)

    N. L Vaquero

    2010-09-01

    Full Text Available La enfermedad de Hansen producida por el Mycobacterium leprae, es una enfermedad infecciosa cuyo amplio espectro clínico e inmunopatológico se correlaciona con los diferentes patrones de respuesta Th1/Th2. La activación preferencial de esas subpoblaciones de linfocitos T CD4 juega un rol importante en su patogenia y constituye un modelo natural de esa dicotomía de la respuesta inmune. Ambas formas polares de la lepra presentan un perfil definido de secreción de citoquinas: Th1 (IL2 e IFN? en el polo tuberculoide y Th2 (IL4, IL5, IL10 en el polo lepromatoso. En el primer caso, la respuesta celular adecuada estimula la activación macrofágica y lleva a la destrucción del bacilo. Las lesiones son escasas y limitadas a la piel y nervios periféricos. En el segundo en cambio, la respuesta celular es casi nula y los bacilos se multiplican descontroladamente dentro de los macrófagos, llevando a la diseminación de las lesiones y afectación de otros órganos. La inmunidad humoral está exacerbada y hay un alto nivel de anticuerpos que no pueden eliminar el germen intracelular. Los factores que determinan la diferenciación hacia una respuesta Th1 ó Th2 no se han esclarecido totalmente. Se han postulado varias hipótesis que hacen referencia a factores genéticos, prevalencia de citoquinas en el microambiente celular, disfunción macrofágica; alteración en los receptores Toll de la inmunidad innata, en la expresión de moléculas coestimulatorias, etc En los últimos años se han descubierto nuevas subpoblaciones de linfocitos, (CD4+ CD25+, Tr1, Th3 y Th17 que estarían implicadas en la desregulación de estas respuestas inmunes.Hansen' disease, caused by Mycobacterium leprae, is an infectious illness whose wide clinical and immunopathologic spectrum correl with different Th1/Th2 responses patterns. The prefferencial activation of the CD4 T cells subset play an important rol in it's pathogenia and provides a natural model of that balance

  8. Delayed Activation Kinetics of Th2- and Th17 Cells Compared to Th1 Cells.

    Science.gov (United States)

    Duechting, Andrea; Przybyla, Anna; Kuerten, Stefanie; Lehmann, Paul V

    2017-09-12

    During immune responses, different classes of T cells arise: Th1, Th2, and Th17. Mobilizing the right class plays a critical role in successful host defense and therefore defining the ratios of Th1/Th2/Th17 cells within the antigen-specific T cell repertoire is critical for immune monitoring purposes. Antigen-specific Th1, Th2, and Th17 cells can be detected by challenging peripheral blood mononuclear cells (PBMC) with antigen, and establishing the numbers of T cells producing the respective lead cytokine, IFN-γ and IL-2 for Th1 cells, IL-4 and IL-5 for Th2, and IL-17 for Th-17 cells, respectively. Traditionally, these cytokines are measured within 6 h in flow cytometry. We show here that 6 h of stimulation is sufficient to detect peptide-induced production of IFN-γ, but 24 h are required to reveal the full frequency of protein antigen-specific Th1 cells. Also the detection of IL-2 producing Th1 cells requires 24 h stimulation cultures. Measurements of IL-4 producing Th2 cells requires 48-h cultures and 96 h are required for frequency measurements of IL-5 and IL-17 secreting T cells. Therefore, accounting for the differential secretion kinetics of these cytokines is critical for the accurate determination of the frequencies and ratios of antigen-specific Th1, Th2, and Th17 cells.

  9. Role of Th1 and Th2 cells in autoimmune demyelinating disease

    Directory of Open Access Journals (Sweden)

    Nagelkerken L.

    1998-01-01

    Full Text Available Evidence is accumulating that Th1 cells play an important role in the development of multiple sclerosis (MS and experimental allergic encephalomyelitis (EAE, whereas Th2 cells contribute to recovery from disease. A major determinant in the development of Th1 and Th2 cells is the type of antigen-presenting cell (APC involved and its functional characteristics, e.g., the production of interleukin-12. Therefore, modulation of APC might interfere with the development of Th1 type responses and as such be beneficial for MS and EAE. The potential of cytokines, in particular interleukin-10, and glucocorticoids to exert a selective effect on APC, and as a consequence to affect the Th1-Th2 balance in EAE, is discussed

  10. Effect of Malnutrition on the Expression of Cytokines Involved in Th1 Cell Differentiation

    Science.gov (United States)

    González-Torres, Cristina; González-Martínez, Haydeé; Miliar, Angel; Nájera, Oralia; Graniel, Jaime; Firo, Verónica; Alvarez, Catalina; Bonilla, Edmundo; Rodríguez, Leonor

    2013-01-01

    Malnutrition is a common cause of secondary immune deficiency and has been linked to an increased susceptibility to infection in humans. Malnutrition specifically affects T-cell-mediated immune responses. The aim of this study was to assess in lymphocytes from malnourished children the expression levels of IL-12, IL-18 and IL-21, molecules that induce the differentiation of T cells related to the immunological cellular response (Th1 response) and the production of cytokines related to the immunological cellular response (Th1 cytokines). We found that the expression levels of IL-12, IL-18 and IL-21 were significantly diminished in malnourished children compared to well-nourished children and were coincident with lower plasmatic levels of IL-2 and IFN-γ (Th1 cytokines). In this study, we show for the first time that the gene expression and intracellular production of cytokines responsible for Th1 cell differentiation (IL-12, IL-18 and IL-21) are diminished in malnourished children. As expected, this finding was related to lower plasmatic levels of IL-2 and IFN-γ. The decreased expression of Th1 cytokines observed in this study may contribute to the deterioration of the immunological Type 1 (cellular) response. We hypothesize that the decreased production of IL-12, IL-18 and IL-21 in malnourished children contributes to their inability to eradicate infections. PMID:23429441

  11. 7 CFR 400.406 - Insurance provider responsibilities.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 6 2010-01-01 2010-01-01 false Insurance provider responsibilities. 400.406 Section 400.406 Agriculture Regulations of the Department of Agriculture (Continued) FEDERAL CROP INSURANCE CORPORATION, DEPARTMENT OF AGRICULTURE GENERAL ADMINISTRATIVE REGULATIONS General Administrative Regulations...

  12. The Debate on the Moral Responsibilities of Online Service Providers.

    Science.gov (United States)

    Taddeo, Mariarosaria; Floridi, Luciano

    2016-12-01

    Online service providers (OSPs)-such as AOL, Facebook, Google, Microsoft, and Twitter-significantly shape the informational environment (infosphere) and influence users' experiences and interactions within it. There is a general agreement on the centrality of OSPs in information societies, but little consensus about what principles should shape their moral responsibilities and practices. In this article, we analyse the main contributions to the debate on the moral responsibilities of OSPs. By endorsing the method of the levels of abstract (LoAs), we first analyse the moral responsibilities of OSPs in the web (LoAIN). These concern the management of online information, which includes information filtering, Internet censorship, the circulation of harmful content, and the implementation and fostering of human rights (including privacy). We then consider the moral responsibilities ascribed to OSPs on the web (LoAON) and focus on the existing legal regulation of access to users' data. The overall analysis provides an overview of the current state of the debate and highlights two main results. First, topics related to OSPs' public role-especially their gatekeeping function, their corporate social responsibilities, and their role in implementing and fostering human rights-have acquired increasing relevance in the specialised literature. Second, there is a lack of an ethical framework that can (a) define OSPs' responsibilities, and (b) provide the fundamental sharable principles necessary to guide OSPs' conduct within the multicultural and international context in which they operate. This article contributes to the ethical framework necessary to deal with (a) and (b) by endorsing a LoA enabling the definition of the responsibilities of OSPs with respect to the well-being of the infosphere and of the entities inhabiting it (LoAFor).

  13. The preventive effects of natural adjuvants, G2 and G2F on tracheal responsiveness and serum IL-4 and IFN-γ (th1/th2 balance in sensitized guinea pigs

    Directory of Open Access Journals (Sweden)

    Mohammad Hossein Boskabady

    2014-07-01

    Full Text Available OBJECTIVE:The effects of natural adjuvants on lung inflammation and tracheal responsiveness were examined in sensitized guinea pigs.METHODS:The responses of guinea pig tracheal chains and the serum levels of interleukin-4 and interferon-gamma were examined in control pigs and three other groups of guinea pigs: the sensitized group and two other sensitized groups treated with either adjuvant G2 or adjuvant G2F (n = 7 for each group. Sensitization of the animals was achieved by injection and inhalation of ovalbumin.RESULTS:The results showed that sensitized animals had increased tracheal responsiveness and increased serum levels of interleukin-4 and interferon-gamma compared to controls (p<0.05 to p<0.001. Treatments with either G2 or G2F prevented the increase in tracheal responsiveness and serum interleukin-4 (p<0.01 to p<0.001. However, the serum levels of interferon-gamma and the interleukin-4-to-interferon-gamma ratio was increased in the treated groups (p<0.001 for all cases.CONCLUSIONS:These results indicate important preventive effects of two natural adjuvants, particularly G2, on the changes in tracheal responsiveness, serum cytokines and the interleukin-4-to-interferon-gamma ratio (T helper 1/T helper 2 balance in sensitized guinea pigs.

  14. Serum concentrations of GM-CSF and G-CSF correlate with the Th1/Th2 cytokine response in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection

    DEFF Research Database (Denmark)

    Moser, Claus; Jensen, Peter Østrup; Pressler, Tacjana

    2005-01-01

    The inflammation in cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa lung infection is dominated by polymorphonuclear neutrophils (PMNs). There seems to be a relationship between the PMN-dominated inflammation, pronounced antibody production and a Th2-dominated response. Apart fr...

  15. Th1 Differentiation Drives the Accumulation of Intravascular, Non-protective CD4 T Cells during Tuberculosis

    Directory of Open Access Journals (Sweden)

    Michelle A. Sallin

    2017-03-01

    Full Text Available Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. Therefore, we examined the role of Th1-polarizing factors in the generation of protective and non-protective subsets of Mtb-specific Th1 cells. We find that IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73+CXCR3+T-betdim stage, and T-bet prevents deviation of Th1 cells into Th17 cells. Nevertheless, IL- 12/23p40 and T-bet are also essential for the production of a prominent subset of intravascular CX3CR1+KLRG1+ Th1 cells that persists poorly and can neither migrate into the lung parenchyma nor control Mtb growth. Furthermore, T-bet suppresses development of CD69+CD103+ tissue resident phenotype effectors in lung. In contrast, Th1-cell-derived IFN-γ inhibits the accumulation of intravascular CX3CR1+KLRG1+ Th1 cells. Thus, although IL-12 and T-bet are essential host survival factors, they simultaneously oppose lung CD4 T cell responses at several levels, demonstrating the dual nature of Th1 polarization in tuberculosis.

  16. Th1 Differentiation Drives the Accumulation of Intravascular, Non-protective CD4 T Cells during Tuberculosis.

    Science.gov (United States)

    Sallin, Michelle A; Sakai, Shunsuke; Kauffman, Keith D; Young, Howard A; Zhu, Jinfang; Barber, Daniel L

    2017-03-28

    Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. Therefore, we examined the role of Th1-polarizing factors in the generation of protective and non-protective subsets of Mtb-specific Th1 cells. We find that IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73 + CXCR3 + T-bet dim stage, and T-bet prevents deviation of Th1 cells into Th17 cells. Nevertheless, IL- 12/23p40 and T-bet are also essential for the production of a prominent subset of intravascular CX3CR1 + KLRG1 + Th1 cells that persists poorly and can neither migrate into the lung parenchyma nor control Mtb growth. Furthermore, T-bet suppresses development of CD69 + CD103 + tissue resident phenotype effectors in lung. In contrast, Th1-cell-derived IFN-γ inhibits the accumulation of intravascular CX3CR1 + KLRG1 + Th1 cells. Thus, although IL-12 and T-bet are essential host survival factors, they simultaneously oppose lung CD4 T cell responses at several levels, demonstrating the dual nature of Th1 polarization in tuberculosis. Published by Elsevier Inc.

  17. A nonallergenic birch pollen allergy vaccine consisting of hepatitis PreS-fused Bet v 1 peptides focuses blocking IgG toward IgE epitopes and shifts immune responses to a tolerogenic and Th1 phenotype.

    Science.gov (United States)

    Marth, Katharina; Breyer, Isabella; Focke-Tejkl, Margarete; Blatt, Katharina; Shamji, Mohamed H; Layhadi, Janice; Gieras, Anna; Swoboda, Ines; Zafred, Domen; Keller, Walter; Valent, Peter; Durham, Stephen R; Valenta, Rudolf

    2013-04-01

    Allergen-specific immunotherapy is the only allergen-specific and disease-modifying treatment for allergy. The construction and characterization of a vaccine for birch pollen allergy is reported. Two nonallergenic peptides, PA and PB, derived from the IgE-reactive areas of the major birch pollen allergen Bet v 1 were fused to the hepatitis B surface protein, PreS, in four recombinant fusion proteins containing different numbers and combinations of the peptides. Fusion proteins expressed in Escherichia coli and purified to homogeneity showed a lack of IgE reactivity and allergenic activity when tested with sera and basophils from patients allergic to birch pollen. Compared to Bet v 1 allergen, peptides PA and PB showed reduced T cell activation in PBMCs from allergic patients, whereas PreS fusion proteins induced less IL-5 and more IL-10 and IFN-γ. Immunization of rabbits with the fusion proteins, in particular with a PreS fusion protein 2PAPB-PreS, containing two copies of each peptide, induced high levels of IgG Abs against the major IgE-reactive site on Bet v 1 and related allergens. These IgG Abs inhibited allergic patients' IgE binding to Bet v 1 better than did IgG induced by immunization with complete Bet v 1. Furthermore, 2PAPB-PreS-induced IgG inhibited Bet v 1-induced basophil activation in allergic patients and CD23-facilitated allergen presentation. Our study exemplifies novel beneficial features for a PreS carrier-based peptide vaccine for birch pollen, which, in addition to the established reduction in allergenic activity, include the enhanced focusing of blocking Ab responses toward IgE epitopes, immunomodulatory activity, and reduction of CD23-facilitated allergen presentation.

  18. Provider Behavior Under Global Budgeting and Policy Responses

    Directory of Open Access Journals (Sweden)

    Chao-Kai Chang MD, PhD

    2015-08-01

    Full Text Available Third-party payer systems are consistently associated with health care cost escalation. Taiwan’s single-payer, universal coverage National Health Insurance (NHI adopted global budgeting (GB to achieve cost control. This study captures ophthalmologists’ response to GB, specifically service volume changes and service substitution between low-revenue and high-revenue services following GB implementation, the subsequent Bureau of NHI policy response, and the policy impact. De-identified eye clinic claims data for the years 2000, 2005, and 2007 were analyzed to study the changes in Simple Claim Form (SCF claims versus Special Case Claims (SCCs. The 3 study years represent the pre-GB period, post-GB but prior to region-wise service cap implementation period, and the post-service cap period, respectively. Repeated measures multilevel regression analysis was used to study the changes adjusting for clinic characteristics and competition within each health care market. SCF service volume (low-revenue, fixed-price patient visits remained constant throughout the study period, but SCCs (covering services involving variable provider effort and resource use with flexibility for discretionary billing increased in 2005 with no further change in 2007. The latter is attributable to a 30% cap negotiated by the NHI Bureau with the ophthalmology association and enforced by the association. This study demonstrates that GB deployed with ongoing monitoring and timely policy responses that are designed in collaboration with professional stakeholders can contain costs in a health insurance–financed health care system.

  19. Activated rat hepatic stellate cells influence Th1/Th2 profile in vitro

    Science.gov (United States)

    Xing, Zhi-Zhi; Huang, Liu-Ye; Wu, Cheng-Rong; You, Hong; Ma, Hong; Jia, Ji-Dong

    2015-01-01

    of Th1 cells (1.85% ± 0.48%; P < 0.05). CONCLUSION: Activated rat HSCs lower the Th1/Th2 profile, inhibiting the Th1 response and enhancing the Th2 response, and this may be a novel pathway for liver fibrogenesis. PMID:26109802

  20. Mice lacking IL-12 develop polarized Th1 cells during viral infection

    NARCIS (Netherlands)

    Horzinek, M.C.; Schijns, Virgil E.C.J.; Haagmans, B.L.; Wierda, C.M.; Kruithof, Boudewijn; Heijnen, I.A.; Alber, G.

    1998-01-01

    Studies in IL-12-deficient mice established the necessity for IL-12 to generate a Th1 cytokine response that is often required for elimination of intracellular pathogens. In this study, we demonstrate that mice with a targeted disruption of the IL-12p40 and/or p35 gene effectively control liver

  1. Liver sinusoidal endothelial cells induce immunosuppressive IL-10-producing Th1 cells via the Notch pathway

    NARCIS (Netherlands)

    Neumann, Katrin; Rudolph, Christine; Neumann, Christian; Janke, Marko; Amsen, Derk; Scheffold, Alexander

    2015-01-01

    Under homeostasis, liver sinusoidal endothelial cells (LSECs) shift intrahepatic T-cell responses towards tolerance. However, the role of LSECs in the regulation of T-cell-induced liver inflammation is less clear. Here, we studied the capacity of LSECs to modulate pro-inflammatory Th1-cell

  2. Transcription factor IRF8 controls Th1-like regulatory T-cell function.

    Science.gov (United States)

    Lee, Wonyong; Kim, Hyeong Su; Baek, Song Yi; Lee, Gap Ryol

    2016-11-01

    Recent studies have suggested that regulatory T (Treg) cells comprise a heterogeneous population that regulates various aspects of the immune response, and that Treg cells use the factors that are expressed in their target cells to regulate them. We searched for factors that regulate Th1 response in Treg cells using a meta-analysis. In the process, we discovered that transcription factor interferon regulatory factor 8 (IRF8) was selectively expressed in Treg and Th1 cells. IRF8-deficient Treg cells showed defective expression of CXCR3 and aberrant expression of the Il4 and Il17 genes. Upon treatment with alpha galactosyl-C18-ceramide (αGal-C18-Cer), IRF8-deficient mice showed defective Treg cell recruitment in the liver. Eliciting Th1 immune response by anti-CD40 antibody injection in mice induced IRF8 expression in Treg cells. The expression of IRF8 was induced by Foxp3 in Treg cells. IRF8 had no effect on T-bet expression in Treg and vice versa. Thus, our results strongly suggest that IRF8 controls Th1 immune response in Treg cells independent of T-bet.

  3. Providers' Response to Clinical Decision Support for QT Prolonging Drugs.

    Science.gov (United States)

    Sharma, Sunita; Martijn Bos, J; Tarrell, Robert F; Simon, Gyorgy J; Morlan, Bruce W; Ackerman, Michael J; Caraballo, Pedro J

    2017-09-02

    Commonly used drugs in hospital setting can cause QT prolongation and trigger life-threatening arrhythmias. We evaluate changes in prescribing behavior after the implementation of a clinical decision support system to prevent the use of QT prolonging medications in the hospital setting. We conducted a quasi-experimental study, before and after the implementation of a clinical decision support system integrated in the electronic medical record (QT-alert system). This system detects patients at risk of significant QT prolongation (QTc>500ms) and alerts providers ordering QT prolonging drugs. We reviewed the electronic health record to assess the provider's responses which were classified as "action taken" (QT drug avoided, QT drug changed, other QT drug(s) avoided, ECG monitoring, electrolytes monitoring, QT issue acknowledged, other actions) or "no action taken". Approximately, 15.5% (95/612) of the alerts were followed by a provider's action in the pre-intervention phase compared with 21% (228/1085) in the post-intervention phase (p=0.006). The most common type of actions taken during pre-intervention phase compared to post-intervention phase were ECG monitoring (8% vs. 13%, p=0.002) and QT issue acknowledgment (2.1% vs. 4.1%, p=0.03). Notably, there was no significant difference for other actions including QT drug avoided (p=0.8), QT drug changed (p=0.06) and other QT drug(s) avoided (p=0.3). Our study demonstrated that the QT alert system prompted a higher proportion of providers to take action on patients at risk of complications. However, the overall impact was modest underscoring the need for educating providers and optimizing clinical decision support to further reduce drug-induced QT prolongation.

  4. THE ROLE OF Th1 AND Th2 CELLS IN ATOPIC AND AUTOIMMUNE DISEASES

    Directory of Open Access Journals (Sweden)

    Snežana Cekić

    2005-12-01

    Full Text Available –helper cells can be divided into two distinct subtypes of effector cells based on the profile of cytokines they produce. Th1 cells produce interferon– γ (IFN– γ and tumor necrosis factor β (TNF– β, and are associated with cell– mediated responses, particularly with resistance to intracellular pathogens (bacteria, parasites, yeasts and viruses. In contrast, Th2 . cells produce IL– 4, IL– 5, IL– 9 and IL– 13. Th2 cells are involved in antibody responses and IgE production, as well as tissue fibrosis, and eosinophilia. Th2 responses are important in the resistance to infection with helminth parasites. Although both Th responses are protective against certain infectious pathogens, they can themselves be pathogenic: Th1 cell responses can mediate autoimmune diseases, whereas dysregulation of Th2 responses is implicated inatopic diseases (allergic rhinitis, asthma, atopic eczema, food allergy and anaphylaxis. The recent progress in our understanding of the mechanism of initiation and control of Th1 and Th2 cell responses will eventually lead to new therapeutic strategies.

  5. Cigarette smoke induction of Interleukin-27/WSX-1 regulates the differentiation of Th1 and Th17 cells in a smoking mouse model of emphysema

    Directory of Open Access Journals (Sweden)

    Shi-Lin Qiu

    2016-12-01

    Full Text Available IFN-γ-producing CD4+T (Th1 cells and IL-17-producing CD4+T (Th17 cells play a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD. However, the immune regulation between Th1 and Th17 cells remains unclear. Previous studies have demonstrated that IL-27/WSX-1 exerted pro- or anti-inflammatory effects in many acute inflammatory diseases by modulating T cell-mediated immune response, but little was known about its role in chronic inflammatory disease, especially in smoking-related lung diseases. Considering IL-27 is an important regulator in T lymphocytes immune responses and was markedly increased in patients with COPD, we hypothesize that IL-27/WSX-1 may exert immuno-regulatory effects on the differentiation of Th1 and Th17 cells in smoking-related COPD. In this study, we aimed to evaluate the expression of IL-27 in patients with COPD and explore the role of IL-27/WSX-1 on Th1 and Th17 cells differentiation in a smoking mouse model of emphysema. We found that elevated expression of IL-27 was associated with increased proportion of Th1 cells and Th17 cells in patients with COPD and demonstrated parallel findings in cigarette smoke exposed mice. In addition, cigarette smoke exposure up-regulated the expression of IL-27R (WSX-1 by naive CD4+T cells in mice. In vitro, IL-27 significantly augmented the secretion of IFN-γ by naive CD4+ T cells via a T-bet, p-STAT1 and p-STAT3-dependent manner, but inhibited the production of IL-17 by a ROR-γt and p-STAT1-dependent way. Furthermore, anti-IL27 treatment dramatically decreased the expression of IFN-γ-producing CD+4 T cells in cigarette smoke exposed mice. These findings proposed that IL-27 has functions for promoting the expression of Th1 cells but inhibiting the expression of Th17 cells in vitro and IL-27 neutralization attenuated Th1-mediated inflammation in vivo, suggesting targeting IL-27/WSX-1 may provide a new therapeutic approach for smoking-related COPD.

  6. Sex-Based Selectivity of PPARγ Regulation in Th1, Th2, and Th17 Differentiation

    Directory of Open Access Journals (Sweden)

    Hong-Jai Park

    2016-08-01

    Full Text Available Peroxisome proliferator-activated receptor gamma (PPARγ has recently been recognized to regulate adaptive immunity through Th17 differentiation, Treg functions, and TFH responses. However, its role in adaptive immunity and autoimmune disease is still not clear, possibly due to sexual differences. Here, we investigated in vitro treatment study with the PPARγ agonist pioglitazone to compare Th1, Th2, and Th17 differentiation in male and female mouse splenic T cells. Pioglitazone treatment significantly inhibited various effector T cell differentiations including Th1, Th2, and Th17 cells from female naïve T cells, but it selectively reduced IL-17 production in male Th17 differentiation. Interestingly, pioglitazone and estradiol (E2 co-treatment of T cells in males inhibited differentiation of Th1, Th2, and Th17 cells, suggesting a mechanism for the greater sensitivity of PPARγ to ligand treatment in the regulation of effector T cell differentiation in females. Collectively, these results demonstrate that PPARγ selectively inhibits Th17 differentiation only in male T cells and modulates Th1, Th2, and Th17 differentiation in female T cells based on different level of estrogen exposure. Accordingly, PPARγ could be an important immune regulator of sexual differences in adaptive immunity.

  7. Efficacy of Leishmania donovani trypanothione reductase, identified as a potent Th1 stimulatory protein, for its immunogenicity and prophylactic potential against experimental visceral leishmaniasis.

    Science.gov (United States)

    Khare, Prashant; Jaiswal, Anil Kumar; Tripathi, Chandra Dev Pati; Joshi, Sumit; Sundar, Shyam; Dube, Anuradha

    2014-03-01

    In visceral leishmaniasis (VL), Th1-type of immune responses play an important role which correlates with recovery from and resistance to disease resulting in lifelong immunity. Based on this rationale, the soluble leishmanial antigens that elicit cellular responses in peripheral blood mononuclear cells (PBMCs) from cured Leishmania patients were characterized through immunoproteomic approach which led to the identification of trypanothione reductase (TPR) (a cytosolic enzyme explored as a drug target), as one of the potent Th1 stimulatory protein. In this study, the immunogenicity of recombinant Leishmania donovani TPR (rLdTPR) was assessed in PBMCs of cured Leishmania-infected patients/hamsters and further evaluated its prophylactic efficacy against L. donovani challenges in hamsters. Substantial proliferative responses to rLdTPR, as compared to soluble L. donovani antigen, were observed in Leishmania-infected cured patients as well as in hamsters. Moreover, rLdTPR reasonably stimulated PBMCs of cured Leishmania patients to produce IFNγ, IL-12, and TNF-α but not IL-4 or IL-10. On the other hand, the protein downregulated LPS-induced IL-10 as well as soluble L. donovani antigen-induced IL-4 production in PBMCs of Leishmania patients. In case of cured hamsters, rLdTPR generates mixed Th1 and Th2 immune response. Vaccination with rLdTPR along with Bacillus Calmette-Guerin (BCG) was able to provide considerably good prophylactic efficacy (~60%) against L. donovani challenge in hamsters. The efficacy was supported by the increased inducible NO synthase mRNA transcript and Th1-type cytokines IFNγ, IL-12, and TNF-α and downregulation of IL-4, IL-10, and TGF-β. Since rLdTPR protein is an important target, further attempts towards determination of immunodominant regions for designing fusion peptides may be taken up to optimize its prophylactic efficacy.

  8. Modulation of Dendritic Cell Activation and Subsequent Th1 Cell Polarization by Lidocaine

    Science.gov (United States)

    Chung, Yeonseok

    2015-01-01

    Dendritic cells play an essential role in bridging innate and adaptive immunity by recognizing cellular stress including pathogen- and damage-associated molecular patterns and by shaping the types of antigen-specific T cell immunity. Although lidocaine is widely used in clinical settings that trigger cellular stress, it remains unclear whether such treatment impacts the activation of innate immune cells and subsequent differentiation of T cells. Here we showed that lidocaine inhibited the production of IL–6, TNFα and IL–12 from dendritic cells in response to toll-like receptor ligands including lipopolysaccharide, poly(I:C) and R837 in a dose-dependent manner. Notably, the differentiation of Th1 cells was significantly suppressed by the addition of lidocaine while the same treatment had little effect on the differentiation of Th17, Th2 and regulatory T cells in vitro. Moreover, lidocaine suppressed the ovalbumin-specific Th1 cell responses in vivo induced by the adoptive transfer of ovalbumin-pulsed dendritic cells. These results demonstrate that lidocaine inhibits the activation of dendritic cells in response to toll-like receptor signals and subsequently suppresses the differentiation of Th1 cell responses. PMID:26445366

  9. Inhibition of Th1 and Th17 Cells by Medicinal Plants and Their Derivatives: A Systematic Review.

    Science.gov (United States)

    Asadi-Samani, Majid; Bagheri, Nader; Rafieian-Kopaei, Mahmoud; Shirzad, Hedayatollah

    2017-08-01

    Searching for new natural drugs that are capable of targeting Th1 and Th17 may lead to development of more effective treatments for inflammatory and autoimmune diseases. Most of the natural drugs can be derived from plants that are used in traditional medicine and folk medicine. The aim of this systematic review is to identify and introduce plants or plant derivatives that are effective on inflammatory diseases by inhibiting Th1 and Th17 responses. To achieve this purpose, the search terms herb, herbal medicine, herbal drug, medicinal plant, phytochemical, traditional Chinese medicine, Ayurvedic medicine, natural compound, inflammation, inflammatory diseases, Th1, Th17, T helper 1 or T helper 17 were used separately in Title/Keywords/Abstract in Web of Science and PubMed databases. In articles investigating the effect of the medicinal plants and their derivatives in inhibiting Th1 and Th17 cells, the effects of eight extracts of the medicinal plants, 21 plant-based compounds and some of their derivatives, and eight drugs derived from the medicinal plants' compounds in inhibiting Th1 and Th17 cells were reviewed. The results showed that medicinal plants and their derivates are able to suppress Th17 and Th1 T cell functions as well as cytokine secretion and differentiation. The results can be used to produce herbal drugs that suppress Th, especially Th17, responses. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  10. COMPENSATION LOW-FREQUENCY ERRORS IN TH-1 SATELLITE

    Directory of Open Access Journals (Sweden)

    J. Wang

    2016-06-01

    Full Text Available The topographic mapping products at 1:50,000 scale can be realized using satellite photogrammetry without ground control points (GCPs, which requires the high accuracy of exterior orientation elements. Usually, the attitudes of exterior orientation elements are obtained from the attitude determination system on the satellite. Based on the theoretical analysis and practice, the attitude determination system exists not only the high-frequency errors, but also the low-frequency errors related to the latitude of satellite orbit and the time. The low-frequency errors would affect the location accuracy without GCPs, especially to the horizontal accuracy. In SPOT5 satellite, the latitudinal model was proposed to correct attitudes using approximately 20 calibration sites data, and the location accuracy was improved. The low-frequency errors are also found in Tian Hui 1 (TH-1 satellite. Then, the method of compensation low-frequency errors is proposed in ground image processing of TH-1, which can detect and compensate the low-frequency errors automatically without using GCPs. This paper deal with the low-frequency errors in TH-1: First, the analysis about low-frequency errors of the attitude determination system is performed. Second, the compensation models are proposed in bundle adjustment. Finally, the verification is tested using data of TH-1. The testing results show: the low-frequency errors of attitude determination system can be compensated during bundle adjustment, which can improve the location accuracy without GCPs and has played an important role in the consistency of global location accuracy.

  11. Responses evoked by a vestibular implant providing chronic stimulation.

    Science.gov (United States)

    Thompson, Lara A; Haburcakova, Csilla; Gong, Wangsong; Lee, Daniel J; Wall, Conrad; Merfeld, Daniel M; Lewis, Richard F

    2012-01-01

    Patients with bilateral vestibular loss experience dehabilitating visual, perceptual, and postural difficulties, and an implantable vestibular prosthesis that could improve these symptoms would be of great benefit to these patients. In previous work, we have shown that a one-dimensional, unilateral canal prosthesis can improve the vestibulooccular reflex (VOR) in canal-plugged squirrel monkeys. In addition to the VOR, the potential effects of a vestibular prosthesis on more complex, highly integrative behaviors, such as the perception of head orientation and posture have remained unclear. We tested a one-dimensional, unilateral prosthesis in a rhesus monkey with bilateral vestibular loss and found that chronic electrical stimulation partially restored the compensatory VOR and also that percepts of head orientation relative to gravity were improved. However, the one-dimensional prosthetic stimulation had no clear effect on postural stability during quiet stance, but sway evoked by head-turns was modestly reduced. These results suggest that not only can the implementation of a vestibular prosthesis provide partial restitution of VOR but may also improve perception and posture in the presence of bilateral vestibular hypofunction (BVH). In this review, we provide an overview of our previous and current work directed towards the eventual clinical implementation of an implantable vestibular prosthesis.

  12. Nursing Home Response to Nursing Home Compare: The Provider Perspective.

    Science.gov (United States)

    Perraillon, Marcelo Coca; Brauner, Daniel J; Konetzka, R Tamara

    2017-08-01

    Nursing Home Compare (NHC) publishes composite quality ratings of nursing homes based on a five-star rating system, a system that has been subject to controversy about its validity. Using in-depth interviews, we assess the views of nursing home administrators and staff on NHC and unearth strategies used to improve ratings. Respondents revealed conflicting goals and strategies. Although nursing home managers monitor the ratings and expend effort to improve scores, competing goals of revenue maximization and avoidance of litigation often overshadow desire to score well on NHC. Some of the improvement strategies simply involve coding changes that have no effect on resident outcomes. Many respondents doubted the validity of the self-reported staffing data and stated that lack of risk adjustment biases ratings. Policy makers should consider nursing home incentives when refining the system, aiming to improve the validity of the self-reported domains to provide incentives for broader quality improvement.

  13. Starfish, Asterias amurensis and Asterina pectinifera, as potential sources of Th1 immunity-stimulating adjuvants.

    Science.gov (United States)

    Kawase, Osamu; Goo, Youn-Kyoung; Jujo, Hayato; Nishikawa, Yoshifumi; Xuan, Xuenan

    2011-02-01

    Saponin is the generic name of steroid or triterpene glycosides, and the capacities of some saponins to stimulate both Th1 immune response and production of cytotoxic T cells are useful as vaccine components against intracellular pathogens. Because saponins have been found commonly in starfish, we assessed the potential of starfish, Asterias amurensis and Asterina pectinifera, as adjuvant sources. Crude starfish saponins had hemolytic activities (EC(50)=10 to 100 µg/ml) and thin layer chromatography indicated heterogeneity of their constituents. When starfish saponis were subcutaneously injected into mice with ovalbumin (OVA), OVA-specific IgG, especially IgG2a instead of IgG1 was produced in mouse blood, suggesting starfish saponins stimulated Th1 type immunity and they were potential sources of new adjuvants.

  14. Th-1, Th-2 Cytokines Profile among Madurella mycetomatis Eumycetoma Patients.

    Directory of Open Access Journals (Sweden)

    Amre Nasr

    2016-07-01

    Full Text Available Eumycetoma is a progressive and destructive chronic granulomatous subcutaneous inflammatory disease caused by certain fungi, the most common being Madurella mycetomatis. The host defence mechanisms against fungi usually range from an early non-specific immune response to activation and induction of specific adaptive immune responses by the production of Th-1 and Th-2 cytokines. The aim of this study is to determine the levels of Th-1 and Th-2 cytokines in patients infected with Madurella mycetomatis, and the association between their levels and disease prognosis. This is a descriptive cross-sectional study conducted at the Mycetoma Research Centre, University of Khartoum, Sudan, where 70 patients with confirmed M. mycetomatis eumycetoma were enrolled; 35 with, and 35 without surgical excision. 70 healthy individuals from mycetoma endemic areas were selected as controls. The levels of serum cytokines were determined by cytometric bead array technique. Significantly higher levels of the Th-1 cytokines (IFN-γ, TNF-α, IL-1β and IL-2 were recorded in patients treated with surgical excision, compared to those treated without surgical excision. In contrast, the Th-2 cytokines (IL-4, IL-5, IL-6 and IL-10 were significantly lower in patients treated with surgical excision compared to those treated without surgical excision. In conclusion, the results of this study suggest that cell-mediated immunity can have a role to play in the pathogenesis of eumycetoma.

  15. Key Aspects of Providing Healthcare Services in Disaster Response Stage.

    Science.gov (United States)

    Pourhosseini, Samira Sadat; Ardalan, Ali; Mehrolhassani, Mohammad Hossien

    2015-01-01

    Health care management in disasters is one of the main parts of disaster management. Health in disasters is affected by performance of various sectors, and has an interactive impact on various aspects of disaster management. The aim of this study was to identify the most important themes affecting the healthcare management in disaster. In this qualitative study with a content analysis approach, in-depth interviews in two steps with 30 disaster experts and managers were conducted to collect the data. Eleven themes affecting healthcare management in disasters were identified. These themes were related to human resources management, resources management, victims' management transfer, environmental hygiene monitoring, nutrition management, mental health control, inter-agency coordination, training, technology management, information and communication management, and budget management. Providing effective health care service in disasters requires a comprehensive look at the various aspects of disaster management. Effective factors on the success of healthcare in disaster are not limited to the scope of healthcare. There should be a close relationship and interaction between different sectors of disaster management.

  16. Suppression of Th1-mediated autoimmunity by embryonic stem cell-derived dendritic cells.

    Directory of Open Access Journals (Sweden)

    Tokunori Ikeda

    Full Text Available We herein demonstrate the immune-regulatory effect of embryonic stem cell-derived dendritic cells (ES-DCs using two models of autoimmune disease, namely non-obese diabetic (NOD mice and experimental autoimmune encephalomyelitis (EAE. Treatment of pre-diabetic NOD mice with ES-DCs exerted almost complete suppression of diabetes development during the observation period for more than 40 weeks. The prevention of diabetes by ES-DCs was accompanied with significant reduction of insulitis and decreased number of Th1 and Th17 cells in the spleen. Development of EAE was also inhibited by the treatment with ES-DCs, and the therapeutic effect was obtained even if ES-DCs were administrated after the onset of clinical symptoms. Treatment of EAE-induced mice with ES-DCs reduced the infiltration of inflammatory cells into the spinal cord and suppressed the T cell response to the myelin antigen. Importantly, the ES-DC treatment did not affect T cell response to an exogenous antigen. As the mechanisms underlying the reduction of the number of infiltrating Th1 cells, we observed the inhibition of differentiation and proliferation of Th1 cells by ES-DCs. Furthermore, the expression of VLA-4α on Th1 cells was significantly inhibited by ES-DCs. Considering the recent advances in human induced pluripotent stem cell-related technologies, these results suggest a clinical application for pluripotent stem cell-derived dendritic cells as a therapy for T cell-mediated autoimmune diseases.

  17. [Circulating levels of Th1- and Th2-chemokines increase in patients with early syphilis].

    Science.gov (United States)

    Zhu, Anyou; Wang, Chenchen; Sun, Hong; Han, Hongfang; Wang, Fengchao; Zhang, Lunjun; Hu, Jianguo

    2017-03-01

    Objective To study the changes of plasma T helper type I (Th1)-and Th2-chemokine levels and analyze their roles in immune response and pathogenesis of early syphilis. Methods Heparin-anticoagulated peripheral blood was collected from 56 patients with early syphilis (primary syphilis, PS, n=22; secondary syphilis, SS, n=34) and healthy controls (HC, n=20). The levels of plasma Th1 chemokines including monokine induced by interferon-γ (MIG), interferon-γ inducible protein-10 (IP-10), interferon-inducible T-cell α chemoattractant (I-TAC) and Th2 chemokines including thymus-and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) were examined using ELISA. Meanwhile, the levels of plasma cytokines (IFN-γ, IL-4 and TNF-α) and C-reactive protein (CRP) were detected. Results The levels of plasma MIG, IP-10 and TARC, MDC in the patients with PS and SS were significantly higher than those in the healthy controls. Moreover, the level of I-TAC in the patients with SS was significantly higher than that in the healthy controls. In particular, the levels of plasma Th1 chemokines (MIG, IP-10 and I-TAC) in the patients with SS significantly increased compared with those with PS. However, no significant difference was observed in the levels of plasma Th2 chemokines (TARC and MDC) between the patients with PS and SS. The correlation analysis showed that there was an obvious positive correlation between IP-10 and MIG, I-TAC, IFN-γ, TNF-α levels in the patients with early syphilis. Furthermore, the levels of MIG and IP-10 were positively associated with plasma CRP in the patients with early syphilis. Conclusion Both Th1 chemokines and Th2 chemokines are involved in immune response of early syphilis.

  18. P2X7 receptor drives Th1 cell differentiation and controls the follicular helper T cell population to protect against Plasmodium chabaudi malaria.

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    Érika Machado de Salles

    2017-08-01

    Full Text Available A complete understanding of the mechanisms underlying the acquisition of protective immunity is crucial to improve vaccine strategies to eradicate malaria. However, it is still unclear whether recognition of damage signals influences the immune response to Plasmodium infection. Adenosine triphosphate (ATP accumulates in infected erythrocytes and is released into the extracellular milieu through ion channels in the erythrocyte membrane or upon erythrocyte rupture. The P2X7 receptor senses extracellular ATP and induces CD4 T cell activation and death. Here we show that P2X7 receptor promotes T helper 1 (Th1 cell differentiation to the detriment of follicular T helper (Tfh cells during blood-stage Plasmodium chabaudi malaria. The P2X7 receptor was activated in CD4 T cells following the rupture of infected erythrocytes and these cells became highly responsive to ATP during acute infection. Moreover, mice lacking the P2X7 receptor had increased susceptibility to infection, which correlated with impaired Th1 cell differentiation. Accordingly, IL-2 and IFNγ secretion, as well as T-bet expression, critically depended on P2X7 signaling in CD4 T cells. Additionally, P2X7 receptor controlled the splenic Tfh cell population in infected mice by promoting apoptotic-like cell death. Finally, the P2X7 receptor was required to generate a balanced Th1/Tfh cell population with an improved ability to transfer parasite protection to CD4-deficient mice. This study provides a new insight into malaria immunology by showing the importance of P2X7 receptor in controlling the fine-tuning between Th1 and Tfh cell differentiation during P. chabaudi infection and thus in disease outcome.

  19. Effects of PARP-1 Deficiency on Th1 and Th2 Cell Differentiation

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    M. Sambucci

    2013-01-01

    Full Text Available T cell differentiation to effector Th cells such as Th1 and Th2 requires the integration of multiple synergic and antagonist signals. Poly(ADP-ribosylation is a posttranslational modification of proteins catalyzed by Poly(ADP-ribose polymerases (PARPs. Recently, many reports showed that PARP-1, the prototypical member of the PARP family, plays a role in immune/inflammatory responses. Consistently, its enzymatic inhibition confers protection in several models of immune-mediated diseases, mainly through an inhibitory effect on NF-κB (and NFAT activation. PARP-1 regulates cell functions in many types of immune cells, including dendritic cells, macrophages, and T and B lymphocytes. Our results show that PARP-1KO cells displayed a reduced ability to differentiate in Th2 cells. Under both nonskewing and Th2-polarizing conditions, naïve CD4 cells from PARP-1KO mice generated a reduced frequency of IL-4+ cells, produced less IL-5, and expressed GATA-3 at lower levels compared with cells from wild type mice. Conversely, PARP-1 deficiency did not substantially affect differentiation to Th1 cells. Indeed, the frequency of IFN-γ+ cells as well as IFN-γ production, in nonskewing and Th1-polarizing conditions, was not affected by PARP-1 gene ablation. These findings demonstrate that PARP-1 plays a relevant role in Th2 cell differentiation and it might be a target to be exploited for the modulation of Th2-dependent immune-mediated diseases.

  20. Th1 and Th17 Cells in Tuberculosis: Protection, Pathology, and Biomarkers

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    I. V. Lyadova

    2015-01-01

    Full Text Available The outcome of Mycobacterium tuberculosis (Mtb infection ranges from a complete pathogen clearance through asymptomatic latent infection (LTBI to active tuberculosis (TB disease. It is now understood that LTBI and active TB represent a continuous spectrum of states with different degrees of pathogen “activity,” host pathology, and immune reactivity. Therefore, it is important to differentiate LTBI and active TB and identify active TB stages. CD4+ T cells play critical role during Mtb infection by mediating protection, contributing to inflammation, and regulating immune response. Th1 and Th17 cells are the main effector CD4+ T cells during TB. Th1 cells have been shown to contribute to TB protection by secreting IFN-γ and activating antimycobacterial action in macrophages. Th17 induce neutrophilic inflammation, mediate tissue damage, and thus have been implicated in TB pathology. In recent years new findings have accumulated that alter our view on the role of Th1 and Th17 cells during Mtb infection. This review discusses these new results and how they can be implemented for TB diagnosis and monitoring.

  1. Respostas Th1 e Th2 desencadeadas por Mycobacterium tuberculosis virulento em doentes com tuberculose pulmonar

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    Diane J. Ordway

    1998-07-01

    Full Text Available RESUMO: Analisaram-se as respostas Th1 e Th2 desencadeadas por Mycobacterium tuberculosis virulento em doentes com tuberculose pulmonar (TP e em dadores saudáveis vacinados pela BCG. Efectuaramse comparações entre a capacidade que as células T apresentavam para proliferar e para produzir IFN-γ e IL-5 em resposta aos derivados de proteíns purificada (PPD, M. tuberculosis H37Rv (Mtb, e M. tuberculosis H37Rv inactivado pelo calor (hk Mtb.Este estudo demoostrou que os individuos saudá-vels vacínados com BCG evidenciaram um máximo de proliferação e produção de IFN-γ em resposta ao painel de antigénios, e que Mtb vívo destencadeou uma resposta significativamente mais forte que a obtida pelo Mtb inactivado pelo calor. Embora os doentes com tuberculose pulmonary mostrassem respostas medias mais baxies de proliferação e produção de IFN-γ cm relação aos eontrolos saúdaveis, a resposta proliferativa ao PPD não foi significativamente reduzida, enquanto que a resposta ao Mtb e hk Mtb foram, significativas estatisticamitante. Em conclusão na tuberculose pulmonar a produção de IFN-γ pode estar reduzida sem um concomitante aumento de IL-5, confirmandose assim não existir uma mudança de resposta Th1 para Th2 na tuberculose pulmonar.REV PORT PNEUMOL 1998; IV (4:393-402 ABSTRACT: The contribution of Th1 and Th2 responses elicited by virulent Mycobacterium tuberculosis was investigated, in healthy BCG vaccinated individuals and pulmonary tuberculosis patients. Comparisons were made between the T cell capacity to proliferate, produce IFN-γ and IL-5 in response to the soluable antigen purified protein derivative (PPD, live M. tuberculosis H37Rv (Mtb and heat killed M tuberculosis H37Rv (hk Mtb. These studies demonstrated that control individuals showed the strongest mean proliferative and IFN-γ responses towards the antigen antigen panel and Mth elicited a significantly

  2. Dectin-1 activation unlocks IL12A expression and reveals the TH1 potency of neonatal dendritic cells.

    Science.gov (United States)

    Lemoine, Sébastien; Jaron, Barbara; Tabka, Sabrine; Ettreiki, Chourouk; Deriaud, Edith; Zhivaki, Dania; Le Ray, Camille; Launay, Odile; Majlessi, Laleh; Tissieres, Pierre; Leclerc, Claude; Lo-Man, Richard

    2015-11-01

    Early life is characterized by a high susceptibility to infection and a TH2-biased CD4 T-cell response to vaccines. Toll-like receptor (TLR) agonists are currently being implemented as new vaccine adjuvants for TH1 activation, but their translation to the field of pediatric vaccines is facing the impairment of neonatal innate TLR responses. We sought to analyze C-type lectin receptor pathways as an alternative or a coactivator to TLRs for neonatal dendritic cell activation for TH1 polarization. Neonatal monocyte-derived dendritic cells (moDCs) were exposed to various combinations of TLR agonists with or without Dectin-1 agonist. IL-12 and IL-23 responses were analyzed at the transcriptional and protein levels after stimulation. The intracellular pathways triggered by combined TLR plus Dectin-1 stimulation was determined by using pharmacologic inhibitors. The capacity of neonatal moDCs to differentiate naive CD4 TH cells was evaluated in cocultures with heterologous neonatal naive T cells. Curdlan was finally tested as an adjuvant within a subunit tuberculosis vaccine in neonatal mice. Simultaneous coactivation through Dectin-1 and TLRs induced robust secretion of IL-12p70 by neonatal moDCs by unlocking transcriptional control on the p35 subunit of IL-12. Both the spleen tyrosine kinase and Raf-1 pathways were involved in this process, allowing differentiation of neonatal naive T cells toward IFN-γ-producing TH1 cells. In vivo a Dectin-1 agonist as adjuvant was sufficient to induce TH1 responses after vaccination of neonatal mice. Coactivation of neonatal moDCs through Dectin-1 allows TLR-mediated IL-12p70 secretion and TH1 polarization of neonatal T cells. Dectin-1 agonists represent a promising TH1 adjuvant for pediatric vaccination. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  3. CD4 T-cell subsets in Malaria: TH1/TH2 revisited

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    Damian ePerez-Mazliah

    2015-01-01

    Full Text Available CD4+ T cells have been shown to play a central role in immune control of infection with Plasmodium parasites. At the erythrocytic stage of infection, IFN-γ production by CD4+ T cells and CD4+ T-cell help for the B-cell response are required for control and elimination of infected red blood cells. CD4+ T cells are also important for controlling Plasmodium pre-erythrocytic stages through the activation of parasite-specific CD8+ T cells. However, excessive inflammatory responses triggered by the infection have been shown to drive pathology. Early classical experiments demonstrated a biphasic CD4+ T-cell response against erythrocytic stages in mice, in which T helper (Th1 and antibody helper CD4+ T cells appear sequentially during a primary infection. While IFN-γ-producing Th1 cells do play a role in controlling acute infections, and they contribute to acute erythrocytic-stage pathology, it became apparent that a classical Th2 response producing IL-4 is not a critical feature of the CD4+ T cell response during the chronic phase of infection. Rather, effective CD4+ T-cell help for B cells, which can occur in the absence of IL-4, is required to control chronic parasitemia. IL-10, important to counterbalance inflammation and associated with protection from inflammatory-mediated severe malaria in both humans and experimental models, was originally considered be produced by CD4+ Th2 cells during infection. We review the interpretations of CD4+ T cell responses during Plasmodium infection, proposed under the original Th1/Th2 paradigm, in light of more recent advances, including the identification of multifunctional T cells such as Th1 cells co-expressing IFN-γ and IL-10, the identification of follicular helper T cells (Tfh as the predominant CD4+ T helper subset for B cells, and the recognition of inherent plasticity in the fates of different CD4+ T cells.

  4. 20 CFR 665.300 - What are rapid response activities and who is responsible for providing them?

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false What are rapid response activities and who is responsible for providing them? 665.300 Section 665.300 Employees' Benefits EMPLOYMENT AND TRAINING... INVESTMENT ACT Rapid Response Activities § 665.300 What are rapid response activities and who is responsible...

  5. Notch and presenilin regulate cellular expansion and cytokine secretion but cannot instruct Th1/Th2 fate acquisition.

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    Chin-Tong Ong

    2008-07-01

    Full Text Available Recent reports suggested that Delta1, 4 and Jagged1, 2 possessed the ability to instruct CD4(+ T cell into selection of Th1 or Th2 fates, respectively, although the underlying mechanism endowing the cleaved Notch receptor with memory of ligand involved in its activation remains elusive. To examine this, we prepared artificial antigen-presenting cells expressing either DLL1 or Jag1. Although both ligands were efficient in inducing Notch2 cleavage and activation in CD4(+ T or reporter cells, the presence of Lunatic Fringe in CD4(+ T cells inhibited Jag1 activation of Notch1 receptor. Neither ligand could induce Th1 or Th2 fate choice independently of cytokines or redirect cytokine-driven Th1 or Th2 development. Instead, we find that Notch ligands only augment cytokine production during T cell differentiation in the presence of polarizing IL-12 and IL-4. Moreover, the differentiation choices of naïve CD4(+ T cells lacking gamma-secretase, RBP-J, or both in response to polarizing cytokines revealed that neither presenilin proteins nor RBP-J were required for cytokine-induced Th1/Th2 fate selection. However, presenilins facilitate cellular proliferation and cytokine secretion in an RBP-J (and thus, Notch independent manner. The controversies surrounding the role of Notch and presenilins in Th1/Th2 polarization may reflect their role as genetic modifiers of T-helper cells differentiation.

  6. Th1 Cell Development Induced by Cysteine Proteinases A and B in Localized Cutaneous Leishmaniasis Due to Leishmania guyanensis

    Science.gov (United States)

    Pascalis, Hervé; Lavergne, Anne; Bourreau, Eliane; Prévot-Linguet, Ghislaine; Kariminia, Amina; Pradinaud, Roger; Rafati, Sima; Launois, Pascal

    2003-01-01

    The cysteine proteinases CPA and CPB from Leishmania major induced Th1 responses in patients with leishmaniasis due to Leishmania guyanensis. Furthermore, cysteine proteinases induced neither interleukin 4 (IL-4) nor IL-13 and low levels of IL-10 in controls and patients. The results suggest that CPs would be quite good candidates for a vaccine against different Leishmania species. PMID:12704171

  7. Lactobacillus Acidophilus Strain L-92 Regulates the Production of Th1 Cytokine as well as Th2 Cytokines

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    Akiko Torii

    2007-01-01

    Conclusions: Oral L-92 administration regulated both Th1 and Th2 cytokine responses, suppressed serum OVA-specific IgE, and induced TGF-β production in PPs. TGF-β is known to be associated with activation of regulatory T (Treg cells. These data suggest that LAB may have immunomodulative effect by Treg cells via TGF-β activity.

  8. File list: DNS.Bld.10.AllAg.Th1_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available DNS.Bld.10.AllAg.Th1_Cells hg19 DNase-seq Blood Th1 Cells SRX069185,SRX201259,SRX20...1263,SRX201270,SRX193612,SRX037118,SRX201262 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/DNS.Bld.10.AllAg.Th1_Cells.bed ...

  9. File list: DNS.Bld.05.AllAg.Th1_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available DNS.Bld.05.AllAg.Th1_Cells hg19 DNase-seq Blood Th1 Cells SRX069185,SRX201259,SRX20...1263,SRX201270,SRX193612,SRX037118,SRX201262 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/DNS.Bld.05.AllAg.Th1_Cells.bed ...

  10. Dendritic Cells Promoted by Ginseng Saponins Drive a Potent Th1 Polarization

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    Masao Takei

    2008-01-01

    Full Text Available Dendritic cells (DC play a pivotal role in the initiation of T-cell-mediated immune responses, making them an attractive cellular adjuvant for use in cancer vaccines. The interaction of T cells with DC is crucial for directing T cell differentiation towards the Th1, Th2 or Th17 type, and several factors determining the direction of the T cell polarization. IL-12 plays a central role in the immune system, not only by augmenting the cytotoxic activity of T cells and NK cells and regulating IFN-γ production, but also by the capacity of IL-12 to promote the development of Th1 cells. Therefore, it is important to identify factors that might affect the differentiation, maturation and function of DC. Ginseng is a medicinal herb widely used in Asian countries, and many of its pharmacological actions are attributed to the ginsenosides. Moreover, T-cadinol and calamenene are sesquterpenes isolated from the heartwood of Cryptomeria japonica being pharmacologically active substances. We investigated whether M1 and M4, end products of steroidal ginseng saponins metabolized in digestive tracts, as well as T-cadinol and calamenene can drive DC maturation from human monocytes in vitro. Human monocytes were cultured with GM-CSF and IL-4 for 6 days under standard conditions, followed by another 2 days in the presence of M1, M4, T-cadinol or calamenene. The expression levels of CD1a, CD80, CD83, CD86 and HLA-DR on M1-primed DC, M4-primed DC, T-cadinol-primed DC and calamenene-primed DC were enhanced with a concomitant decrease in endocytic activity. M1-primed DC, M4-primed DC, T-cadinol-primed DC or calamenene-primed DC enhanced the T cell stimulatory capacity in an allo MLR (allogeneic mixed lymphocyte reaction. Naïve T cells co-cultured with allogeneic M1-primed DC, M4-primed DC, T-cadinol-primed DC or calamenene-primed DC turned into typical Th1 cells, which produced large quantities of IFN-γ and released small amounts of IL-4 depending on IL-12 secretion

  11. Dendritic Cells Promoted by Ginseng Saponins Drive a Potent Th1 Polarization.

    Science.gov (United States)

    Takei, Masao; Tachikawa, Eiichi; Umeyama, Akemi

    2008-04-18

    Dendritic cells (DC) play a pivotal role in the initiation of T-cell-mediated immune responses, making them an attractive cellular adjuvant for use in cancer vaccines. The interaction of T cells with DC is crucial for directing T cell differentiation towards the Th1, Th2 or Th17 type, and several factors determining the direction of the T cell polarization. IL-12 plays a central role in the immune system, not only by augmenting the cytotoxic activity of T cells and NK cells and regulating IFN-gamma production, but also by the capacity of IL-12 to promote the development of Th1 cells. Therefore, it is important to identify factors that might affect the differentiation, maturation and function of DC. Ginseng is a medicinal herb widely used in Asian countries, and many of its pharmacological actions are attributed to the ginsenosides. Moreover, T-cadinol and calamenene are sesquterpenes isolated from the heartwood of Cryptomeria japonica being pharmacologically active substances. We investigated whether M1 and M4, end products of steroidal ginseng saponins metabolized in digestive tracts, as well as T-cadinol and calamenene can drive DC maturation from human monocytes in vitro. Human monocytes were cultured with GM-CSF and IL-4 for 6 days under standard conditions, followed by another 2 days in the presence of M1, M4, T-cadinol or calamenene. The expression levels of CD1a, CD80, CD83, CD86 and HLA-DR on M1-primed DC, M4-primed DC, T-cadinol-primed DC and calamenene-primed DC were enhanced with a concomitant decrease in endocytic activity. M1-primed DC, M4-primed DC, T-cadinol-primed DC or calamenene-primed DC enhanced the T cell stimulatory capacity in an allo MLR (allogeneic mixed lymphocyte reaction). Naïve T cells co-cultured with allogeneic M1-primed DC, M4-primed DC, T-cadinol-primed DC or calamenene-primed DC turned into typical Th1 cells, which produced large quantities of IFN-gamma and released small amounts of IL-4 depending on IL-12 secretion. In the CTL

  12. Cationic lipid-formulated DNA vaccine against hepatitis B virus: immunogenicity of MIDGE-Th1 vectors encoding small and large surface antigen in comparison to a licensed protein vaccine.

    Directory of Open Access Journals (Sweden)

    Anne Endmann

    Full Text Available Currently marketed vaccines against hepatitis B virus (HBV based on the small (S hepatitis B surface antigen (HBsAg fail to induce a protective immune response in about 10% of vaccinees. DNA vaccination and the inclusion of PreS1 and PreS2 domains of HBsAg have been reported to represent feasible strategies to improve the efficacy of HBV vaccines. Here, we evaluated the immunogenicity of SAINT-18-formulated MIDGE-Th1 vectors encoding the S or the large (L protein of HBsAg in mice and pigs. In both animal models, vectors encoding the secretion-competent S protein induced stronger humoral responses than vectors encoding the L protein, which was shown to be retained mainly intracellularly despite the presence of a heterologous secretion signal. In pigs, SAINT-18-formulated MIDGE-Th1 vectors encoding the S protein elicited an immune response of the same magnitude as the licensed protein vaccine Engerix-B, with S protein-specific antibody levels significantly higher than those considered protective in humans, and lasting for at least six months after the third immunization. Thus, our results provide not only the proof of concept for the SAINT-18-formulated MIDGE-Th1 vector approach but also confirm that with a cationic-lipid formulation, a DNA vaccine at a relatively low dose can elicit an immune response similar to a human dose of an aluminum hydroxide-adjuvanted protein vaccine in large animals.

  13. IFNbeta-1a treatment and reestablishment of Th1 regulation in MS patients: dose effects.

    Science.gov (United States)

    Pellegrini, Patrizia; Totaro, Rocco; Contasta, Ida; Berghella, Anna Maria; Russo, Tomassina; Carolei, Antonio; Adorno, Domenico

    2004-01-01

    The authors evaluated the relationships between clinical and pharmacologic parameters and the Th1/Th2/Th3 cytokine network in patients with relapsing-remitting multiple sclerosis treated with differing doses of interferon-beta1a (IFN-beta1a). Their results show that low doses are ineffective but that high doses restore Th1 regulation of the maturation and activation of monocytes, T cells, immature dendritic cells, dendritic cells, and T regulatory cells for central and peripheral self-tolerance. Interaction between interleukin (IL)-10, IL-12 p70, and IL-6 production appears to play an important role in the control of the maturation and activation states of dendritic cells and T regulatory cells, and is at the basis of the benefit of high doses. The results also indicate that the physiologic mechanisms involved in aging help immunologic reestablishment in IFNbeta-1a-treated patients. Finally, it would appear that the failure of IFNbeta-1a therapy to resolve multiple sclerosis completely is due to the suppression of IL-12 p70 mechanisms (responsible for the physiologic deletion of self-reactive cells) in activation conditions, probably by IFNbeta-1a itself.

  14. Modulation of Th1/Th2 balance by Lactobacillus strains isolated from Kimchi via stimulation of macrophage cell line J774A.1 in vitro.

    Science.gov (United States)

    Won, Tae Joon; Kim, Bongjoon; Song, Dong Sup; Lim, Young Tae; Oh, Eun Seul; Lee, Do Ik; Park, Eon Sub; Min, Hyeyoung; Park, So-Young; Hwang, Kwang Woo

    2011-03-01

    Lactobacilli isolated from Kimchi, a Korean traditional food, were tested for their capacity to modulate the T helper (Th) 1/Th2 balance. Ovalbumin (OVA)-sensitized mouse splenocytes were cultured with 26 strains of lactobacilli; the highest IL-12 induction and lowest IL-4 production were then observed in 4 strains, including Lactobacillus plantarum CJLP55, CJLP56, CJLP133, and CJLP136. These strains produced a larger amount of IL-12, which enhances differentiation and activation of Th1 cells, in macrophage cell-lines more than positive control strains L. casei KCTC 3109(T) and L. rhamnosus GG, although they also induced production of IL-10, which is a suppressor of IL-12. Indeed, CJLP133-stimulated macrophages induced production of more Th1 cytokine IFN-γ and less Th2 cytokine IL-4 than KCTC 3109(T) and GG in co-cultivation with T cells. These findings suggest that lactobacilli from Kimchi may modulate the Th1/Th2 balance via macrophage activation in the hypersensitive reaction caused by Th2 cells. Allergic reactions including asthma and atopy are caused by predominance of Th2 response over Th1 response. Lactobacilli isolated from fermented foods such as yogurt, cheese, and Kimchi showed health-promoting activities. The present study indicated that several lactobacilli strains from Kimchi may reduce allergic reactions through macrophage-mediated induction of Th1 response.

  15. Human Blood CD1c+ Dendritic Cells Promote Th1 and Th17 Effector Function in Memory CD4+ T Cells

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    Ingrid M. Leal Rojas

    2017-08-01

    Full Text Available Dendritic cells (DC initiate the differentiation of CD4+ helper T cells into effector cells including Th1 and Th17 responses that play an important role in inflammation and autoimmune disease pathogenesis. In mice, Th1 and Th17 responses are regulated by different conventional (c DC subsets, with cDC1 being the main producers of IL-12p70 and inducers of Th1 responses, while cDC2 produce IL-23 to promote Th17 responses. The role that human DC subsets play in memory CD4+ T cell activation is not known. This study investigated production of Th1 promoting cytokine IL-12p70, and Th17 promoting cytokines, IL-1β, IL-6, and IL-23, by human blood monocytes, CD1c+ DC, CD141+ DC, and plasmacytoid DC and examined their ability to induce Th1 and Th17 responses in memory CD4+ T cells. Human CD1c+ DC produced IL-12p70, IL-1β, IL-6, and IL-23 in response to R848 combined with LPS or poly I:C. CD141+ DC were also capable of producing IL-12p70 and IL-23 but were not as proficient as CD1c+ DC. Activated CD1c+ DC were endowed with the capacity to promote both Th1 and Th17 effector function in memory CD4+ T cells, characterized by high production of interferon-γ, IL-17A, IL-17F, IL-21, and IL-22. These findings support a role for CD1c+ DC in autoimmune inflammation where Th1/Th17 responses play an important role in disease pathogenesis.

  16. Patient race and perceived illness responsibility: effects on provider helping and bias.

    Science.gov (United States)

    Nazione, Samantha; Silk, Kami J

    2013-08-01

    Health care disparities represent a major issue impacting the quality of care in the USA. Provider biases have been identified as contributing to health care disparities. This study examined the helping intentions and biases reported by medical students based on patient race and perceived patient responsibility. The study was guided by the responsibility-affect-helping model (RAHM), which proposes that helping behaviour is a function of perceived responsibility and affect. In a 2 × 3 online experiment, medical students (n = 231) viewed a health chart and dialogue for either a Black or a White patient, in which the dialogue included a manipulation of the patient's rationales for his non-compliance with diet recommendations (responsible, not responsible, no responsibility assigned). After viewing the manipulation, medical students completed measures regarding perceived patient responsibility, affect, intention to help, perceptions of the patient and ethnocentrism. The RAHM was supported, such that increased perceived patient responsibility led to increased provider anger and reduced provider helping intentions, whereas decreased perceived patient responsibility led to increased provider empathy and helping intentions. Additionally, an interaction effect between race and perceived patient responsibility occurred such that bias toward the Black patient was most likely to occur in the control condition. Perceived patient responsibility affects provider helping intentions and interacts with patient race to influence provider perceptions of patient characteristics. Communication on rationales for non-compliance as associated with perceived responsibility may lead to better or worse patient care as providers make attributions about patients based on these factors. © 2013 John Wiley & Sons Ltd.

  17. Th1/Th2 cell dichotomy in acquired immunity to Bordetella pertussis: variables in the in vivo priming and in vitro cytokine detection techniques affect the classification of T cell subsets as Th1, Th2 or Th0

    OpenAIRE

    MILLS, KINGSTON

    1996-01-01

    PUBLISHED In studies of the mechanism of immunity to Bordetella pertussis in a murine respiratory infection model, we have previously demonstrated that natural infection of immunization with a whole cell vaccine induces a potent protective immune response, which is mediated by T-helper type-1 (Th1) cells. In contrast an acellular vaccine generates Th2 cells and is associated with delayed bacterial clearance following respiratory challenge. In the present study we have investigated the appa...

  18. Relationships between Th1 or Th2 iNKT cell activity and structures of CD1d-antigen complexes: meta-analysis of CD1d-glycolipids dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Xavier Laurent

    2014-11-01

    Full Text Available A number of potentially bioactive molecules can be found in nature. In particular, marine organisms are a valuable source of bioactive compounds. The activity of an α-galactosylceramide was first discovered in 1993 via screening of a Japanese marine sponge (Agelas mauritanius. Very rapidly, a synthetic glycololipid analogue of this natural molecule was discovered, called KRN7000. Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000 interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th 1 and Th2 responses with opposing effects. In our work, we carried out molecular dynamics simulations (11.5 µs in total involving eight different ligands (conducted in triplicate in an effort to find out correlation at the molecular level, if any, between chemical modulation of 1 and the orientation of the known biological response, Th1 or Th2. Comparative investigations of human versus mouse and Th1 versus Th2 data have been carried out. A large set of analysis tools was employed including free energy landscapes. One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response. These theoretical tools provide a structural basis for predicting the very different dynamical behaviors of α-glycosphingolipids in CD1d and might aid in the future design of new analogues of 1.

  19. Detection of intracytoplasmic Th1/Th2 cytokine profiles in patients with sepsis and severe sepsis

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    Ahmadinejad Z

    2007-06-01

    Full Text Available Background: Sepsis is the leading cause of death in critically ill patients throughout the world. The incidence is increasing despite the major advances in the development of antimicrobial agents and other supportive treatments. Based on multiple studies, it has been shown that patient outcome depends on Th1 and Th2 cytokine response. Moreover, whenever the Th2 response is predominant, the sepsis is more severe. The aim of this study was to evaluate the correlation between cytokine levels and the severity of sepsis in patients. Methods: A cross-sectional study on the cellular levels of several pro-inflammatory cytokines was carried out in patients with sepsis and severe sepsis. The study included 37 patients (24 men and 13 women, 26 of them had sepsis and 11 had the severe form of sepsis Thirty-seven healthy volunteers served as controls. The average age of the patients was 57 years (±23.3 years, with a range of 21 to 92 years. From the whole blood of the subjects, we separated the monocytes and leukocytes, which were then cultured. Using an ELISA method, we measured levels of IFN- and IL-12 (associated with Th1, and IL-4 and IL-10 (associated with Th2 in the cultured cells with and without cell stimulation. Results: No correlation was found for IFN- production in the cells of patients with sepsis and severe sepsis, regardless of whether the patients had died or survived. However, IL-12 levels were significantly decreased in severe sepsis compared with those of sepsis patients (P=0.048. Furthermore, the cells of expired patients also had significantly decreased IL-12 levels compared with those of surviving patients (P=0.028. We also found that the levels of IFN-, IL-4, and IL-10 were decreased in patients compared with those of controls, which correlated to their production. However, there was no correlation for IL-12 production between the cells of the patients compared with those of the controls. There was also no correlation for

  20. The change in function of Th1 and Th2-lymphocytes and cytokine profile at chronic intoxication of ethanol

    Directory of Open Access Journals (Sweden)

    V.G. Lim and V.F.Grichin

    2012-09-01

    Full Text Available In experiments in non-inbred rats, it has been established that chronic intoxication of ethanol (30 days, total dose – 6.0 LD50 essentially reduces concentration of cytokines IFNγ, IL-2, IL-4, IL-10 in blood, increases concentration of IL-6, reduces an interrelation IFNγ/IL-4 in comparison with the control, suppresses of immune responses, which displays the greater lesion of Th1-cells in comparison with Th2-lymphosytes.

  1. Regulatory role of pro-Th1 and pro-Th2 cytokines in modulating the activity of Th1 and Th2 cells when B cell and macrophages are used as antigen presenting cells

    Directory of Open Access Journals (Sweden)

    Agrewala Javed N

    2006-08-01

    Full Text Available Abstract Background Presence of antigen presenting cells, expression of costimulatory molecules, the strength of first signal and cytokine milieu are quite important in influencing the reactivation of differentiated Th1 and Th2 cells. Results In the present study, we have analyzed the concerted action of pro-Th1 and pro-Th2 cytokines in the presence of B cells, peritoneal and splenic macrophages as antigen presenting cells and varied concentration of first (anti-CD3 Ab and second (B7-1 transfectant signals on the proliferation and cytokine secretion by Th1 and Th2 cells. Interesting observations were made that IFN-γ significantly augmented the secretion of IL-4 by Th2 cells when either B cells or splenic or peritoneal macrophages were used as APC. Further, IFN-γ significantly inhibited the proliferation of Th1 cells only in the presence of peritoneal macrophages. We have also observed that B cells could significantly respond to cytokines to further enhance the proliferation and cytokine release by Th1 and Th2 cells. But not much effect on addition of exogenous cytokines IL-1, IL-4, IL-5, IL-12 was observed on the proliferation of Th1 and Th2 cells in the presence of macrophages. In contrast, both IFN-γ and IL-2 significantly enhanced the production of IL-4 and IL-5 respectively, by Th2 cells in presence of B cells, splenic and peritoneal macrophages. Another important observation was that the addition of B7-1 transfectants in the cultures, which were stimulated with low dose of anti-CD3 Ab significantly, enhanced the proliferation and cytokine secretion. Conclusion This study indicates involvement of different type of APCs, cytokine milieu, dose of first and second signals in a concerted manner in the outcome of the immune response. The significance of this study is that the immunization with antigen along with costimulatory molecules may significantly reduce the dose of antigen and can generate better immune response than antigen alone.

  2. Assessment of a One-Step Intracellular Staining in Th1, Th2 and Th17 Cells of Clinical Samples.

    Science.gov (United States)

    Lin, Xianghua; Luo, Xiaohong; Wang, Ying; Wu, Qiuju; Xiao, Wangxian; Lin, Dijing; Duan, Chaohui

    2015-01-01

    Flow cytometry is a potent tool to dissect the phenotypes and functions of cell subsets by measuring multiple parameters on a single-cell basis. However, intracellular staining may be time consuming and more steps, particularly in cytokines, could be problematic for its use in daily routine or in large cohort testing. Lately, a novel reagent has been developed to perform intracellular staining in one step. The objective of our study was thus to assess this new method in comparison with the reference technique by focusing on CD4+ T-cell subsets such as Th1, Th2, and Th17 cells in clinical samples. Peripheral blood was collected from 10 children with aplastic anemia and 10 healthy volunteers and stained using the reference and one-step methods. Different subsets of CD4+ T-cells, which are defined as Th1, Th2 and Th17 cells, were investigated by flow cytometry. The repetitive experiment was designed to study intraassay precision. Correlations were studied using Pearson's correlation coefficient test. When comparing results obtained with the two techniques, no statistical differences between the percentages of Th1, Th2, and Th17 cells were observed. Besides, a nice correlation between percentages of Th1 cells obtained with the two different methods was identified in the global population (r: 0.777, p cells (r: 0.875, p cells (r: 0.886, p step procedures. Importantly, flow cytometry staining obtained with the one-step method was very robust with a nice intra-assay precision and a better discriminative power and repeatability. With better staining quality and a shorter realization time, one-step intracellular staining may provide an efficient way for daily routine testing of Th1, Th2 and Th17 cells, as well as for further research.

  3. 75 FR 5779 - Notice Providing Agenda for Technical Conference on RTO/ISO Responsiveness

    Science.gov (United States)

    2010-02-04

    ... Energy Regulatory Commission Notice Providing Agenda for Technical Conference on RTO/ISO Responsiveness.... ER09-1050-000, ER09- 1192-000. ISO New England, Inc. and New England Docket No. ER09-1051-000. Power... , (202) 502-8048. Kimberly D. Bose, Secretary. Agenda--Technical Conference on RTO/ISO Responsiveness...

  4. Communication at an online infertility expert forum: provider responses to patients' emotional and informational cues.

    Science.gov (United States)

    Aarts, J W M; van Oers, A M; Faber, M J; Cohlen, B J; Nelen, W L D M; Kremer, J A M; van Dulmen, A M

    2015-01-01

    Online patient-provider communication has become increasingly popular in fertility care. However, it is not known to what extent patients express cues or concerns and how providers respond. In this study, we investigated cues and responses that occur in online patient-provider communication at an infertility-specific expert forum. We extracted 106 threads from the multidisciplinary expert forum of two Dutch IVF clinics. We performed the following analyses: (1) thematic analysis of patients' questions; and (2) rating patients' emotional and informational cues and subsequent professionals' responses using an adaptation of the validated Medical Interview Aural Rating Scale. Frequencies of themes, frequencies of cues and responses, and sequences (what cue is followed by what response) were extracted. Sixty-five infertile patients and 19 providers participated. The most common themes included medication and lifestyle. Patients gave more informational than emotional cues (106 versus 64). Responses to informational cues were mostly adequate (61%). The most common response to emotional cues was empathic acknowledgment (72%). Results indicate that an online expert forum could have a positive effect on patient outcomes, which should guide future research. Offering infertile patients an expert forum to communicate with providers can be a promising supplement to usual care in both providing information and addressing patients' concerns.

  5. Overcoming CD4 Th1 Cell Fate Restrictions to Sustain Antiviral CD8 T Cells and Control Persistent Virus Infection

    Directory of Open Access Journals (Sweden)

    Laura M. Snell

    2016-09-01

    Full Text Available Viral persistence specifically inhibits CD4 Th1 responses and promotes Tfh immunity, but the mechanisms that suppress Th1 cells and the disease consequences of their loss are unclear. Here, we demonstrate that the loss of CD4 Th1 cells specifically leads to progressive CD8 T cell decline and dysfunction during viral persistence. Therapeutically reconstituting CD4 Th1 cells restored CD4 T cell polyfunctionality, enhanced antiviral CD8 T cell numbers and function, and enabled viral control. Mechanistically, combined interaction of PD-L1 and IL-10 by suppressive dendritic cell subsets inhibited new CD4 Th1 cells in both acute and persistent virus infection, demonstrating an unrecognized suppressive function for PD-L1 in virus infection. Thus, the loss of CD4 Th1 cells is a key event leading to progressive CD8 T cell demise during viral persistence with important implications for restoring antiviral CD8 T cell immunity to control persistent viral infection.

  6. Identification of DRG-1 As a Melanoma-Associated Antigen Recognized by CD4+ Th1 Cells.

    Directory of Open Access Journals (Sweden)

    Yukiko Kiniwa

    Full Text Available Immunotherapy has emerged as a promising strategy for the treatment of metastatic melanoma. Clinical studies have demonstrated the feasibility of cancer immunotherapy using tumor antigens recognized by CD8(+ T cells. However, the overall immune responses induced by these antigens are too weak and transient to induce tumor regression in the majority of patients who received immunization. A growing body of evidence suggests that CD4(+ T helper (Th cells play an important role in antitumor immunity. Therefore, the identification of MHC class II-restricted tumor antigens capable of stimulating CD4(+ T cells may provide opportunities for developing effective cancer vaccines. To this end, we describe the identification of developmentally regulated GTP-binding protein 1 (DRG-1 as a melanoma-associated antigen recognized by HLA-DR11-restricted CD4(+ Th1 cells. Epitope mapping analysis showed that the DRG1248-268 epitope of DRG-1 was required for T cell recognition. Reverse transcription-polymerase chain reaction revealed that DRG-1 was highly expressed in melanoma cell lines but not in normal tissues. DRG-1 knockdown by lentiviral-based shRNA suppressed melanoma cell proliferation and soft agar colony formation. Taken together, these data suggest that DRG-1 plays an important role in melanoma cell growth and transformation, indicating that DRG1 may represent a novel target for CD4(+ T cell-mediated immunotherapy in melanoma.

  7. Service Providers' Perceptions of and Responses to Bullying of Individuals with Disabilities

    Science.gov (United States)

    Cook, Erin E.; Nickerson, Amanda B.; Werth, Jilynn M.; Allen, Kathleen P.

    2017-01-01

    A sample of 124 service providers (e.g. mental health professionals, educators, administrators) completed a survey about bullying of individuals with disabilities and the use and perceived effectiveness of resources and strategies to address bullying. Providing support and performing an action in response to bullying were reported to be used more…

  8. Omeprazole-induced acute interstitial nephritis: a possible Th1-Th17-mediated injury?

    Science.gov (United States)

    Berney-Meyer, Linda; Hung, Noelyn; Slatter, Tania; Schollum, John Bw; Kitching, A Richard; Walker, Robert J

    2014-06-01

    Omeprazole is an important cause of drug-induced acute interstitial nephritis (AIN). How omeprazole induces injury is unknown. Detailed clinical assessment of 25 biopsy-proven cases of omeprazole-induced AIN showed that all patients presented with impaired renal function, sterile pyuria with varying amounts of proteinuria but no eosinophiluria and no systemic symptoms to suggest a vasculitis. Histological analyses were characteristic of an acute tubulitis with an inflammatory cellular infiltrate. Using modified Banff scheme criteria, mild tubulitis (t1) was present in 56% of cases, a moderate tubulitis (t2) in 24% of cases, and a severe tubulitis in 20% of cases. Most (78%) of cases had mononuclear cell infiltrates, no significant eosinophilic infiltrates were found, and glomeruli were not involved. Immunostaining for CD4, CD8, IL-17A, IL-17F, Foxp3 and T-bet (T cell subsets), CD20 and CD163 defined the cellular infiltrates. The predominant inflammatory cells were CD4+ lymphocytic aggregates (77% of cases), combined with co-staining of CD4 IL and 17A/F in 44-48% of all cases, suggesting a Th17-mediated inflammatory process. T-bet+ cell infiltrates were present to a lesser degree, suggesting additional Th1 involvement. How omeprazole induces this inflammatory response is unclear, but may include direct effects by IL-17 expressing CD4+ cells on renal tubular cells. This large biopsy series of omeprazole-induced AIN demonstrates the features of acute tubulitis, with significant interstitial infiltrates consistent with immunopathological Th17 and Th1 processes. © 2014 Asian Pacific Society of Nephrology.

  9. Alpha-tocopherol ameliorates experimental autoimmune encephalomyelitis through the regulation of Th1 cells

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    Haikuo Xue

    2016-05-01

    Full Text Available Objective(s: Multiple sclerosis (MS is a serious neurological autoimmune disease, it commonly affects young adults. Vitamin E (Vit E is an important component of human diet with antioxidant activity, which protects the body’s biological systems. In order to assess the effect of Vit E treatment on this autoimmune disease, we established experimental autoimmune encephalomyelitis (EAE, the animal model of MS, and treated EAE with α-tocopherol (AT which is the main content of Vit E. Materials and Methods:Twenty C57BL/6 adult female mice were used and divided into two groups randomly. EAE was induced with myelin oligodendrocyte glycoprotein (MOG, and one group was treated with AT, at a dose of 100 mg/kg on the 3th day post-immunization with MOG, the other group was treated with 1% alcohol. Mice were euthanized on day 14, post-immunization, spleens were removed for assessing splenocytes proliferation and cytokine profile, and spinal cords were dissected to assess the infiltration of inflammatory cells in spinal cord. Results:AT was able to attenuate the severity of EAE and delay the disease progression. H&E staining and fast blue staining indicated that AT reduced the inflammation and the demyelination reaction in the spinal cord. Treatment with AT significantly decreased the proliferation of splenocytes. AT also inhibited the production of IFN-γ (Th1 cytokine, though the other cytokines were only affected slightly. Conclusion:According to the results, AT ameliorated EAE, through suppressing the proliferation of T cells and the Th1 response. AT may be used as a potential treatment for MS.

  10. Role of Th1 and Th2 cells in autoimmune demyelinating disease

    NARCIS (Netherlands)

    Nagelkerken, L.

    1998-01-01

    Evidence is accumulating that Th1 cells play an important role in the development of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), whereas Th2 cells contribute to recovery from disease. A maj or determinant in the development of Th1 and Th2 cells is the type of

  11. Providers perspectives on self-regulation impact their use of responsive feeding practices in child care.

    Science.gov (United States)

    Dev, Dipti A; Speirs, Katherine E; Williams, Natalie A; Ramsay, Samantha; McBride, Brent A; Hatton-Bowers, Holly

    2017-11-01

    Supporting children's self-regulation in eating through caregivers' practice of responsive feeding is paramount to obesity prevention, and while much attention has been given to supporting children's self-regulation in eating through parents' responsive feeding practices in the home setting, little attention has been given to this issue in childcare settings. This qualitative study examines childcare providers' perspectives on using responsive feeding practices with young children (2-5years). Individual semi-structured interviews were conducted with providers until saturation was reached. Data was analyzed using thematic analysis. The final sample included 18 providers who were employed full-time in Head Start or state-licensed center-based childcare programs, cared for children (2-5y), and were directly responsible for serving meals and snacks. Providers were primarily (67%) employed in childcare programs that served children from low-income families and received reimbursement for meals and snacks from the US Department of Agriculture's Child and Adult Care Food Program. Three factors emerged that shaped childcare providers' experiences using responsive feeding practices: the providers' perspectives about whether or not young children can self-regulate food intake, their understanding of Child and Adult Care Food Program (CACFP) portion size regulations, and the availability of food at the center where they worked. Future research should examine how childcare providers' understanding of children's ability to self-regulate their food intake, the appropriate use of the CACFP regulations in relationship to serving sizes, and having food available to offer seconds promotes providers' use of responsive feeding practices in center-based childcare programs and children's dietary behaviors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. The influence of provider characteristics and market forces on response to financial incentives.

    Science.gov (United States)

    O'Neil, Brock; Tyson, Mark; Graves, Amy J; Barocas, Daniel A; Chang, Sam S; Penson, David F; Resnick, Matthew J

    2017-11-01

    Alternative payment models, such as accountable care organizations, use financial incentives as levers for change to facilitate the transition from volume to value. However, implementation raises concerns about adverse changes in market competition and the resultant physician response. We sought to identify physician characteristics and market-level factors associated with variation in response to financial incentives for cancer care that may ultimately be leveraged in risk-shared payment models. Retrospective cohort study of physicians providing minimally invasive bladder cancer procedures to fee-for-service Medicare beneficiaries. We examined the relationship of between-group differences in market-level factors (competition [Herfindahl-Hirschman Index (HHI)] and provider density) and physician-level factors (use of unique billing codes, number of billing codes per patient, and competing financial interest) to responsiveness to financial incentives. Incentive-responsive providers had increased odds (odds ratio [OR], 1.19; 95% CI, 1.04-1.35) of practicing in markets with the highest quartile of provider density but not HHI (OR, 0.96; 95% CI, 0.87-1.05). Incentive-responsive providers were more likely to bill in the highest quartile for unique codes (OR, 1.49; 95% CI, 1.32-1.69) and codes per patient (OR, 1.18; 95% CI, 1.11-1.25) and less likely to have a competing financial interest (OR, 0.76; 95% CI, 0.72-0.81). Responsiveness to financial incentives in cancer care is associated with high market provider density, profit-maximizing billing behavior, and lack of competing financial ownership interests. Identifying physicians and markets responsive to financial incentives may ultimately promote the successful implementation of alternative payment models in cancer care.

  13. Changes of mouse cytokines and Th1/Th2 balance in acute stress induced by millimeter-wave

    Directory of Open Access Journals (Sweden)

    Rong SUN

    2013-11-01

    cytokines increase due to stress, the Th1/Th2 balance drifts significantly to Th1 immune response, thus indicating that immune-regulation may play an important regulatory role in acute stress induced by MMW exposure. DOI: 10.11855/j.issn.0577-7402.2013.10.017

  14. Commensal Gram-negative bacteria prime human dendritic cells for enhanced IL-23 and IL-27 expression and enhanced Th1 development

    NARCIS (Netherlands)

    Smits, Hermelijn H.; van Beelen, Astrid J.; Hessle, Christina; Westland, Robert; de Jong, Esther; Soeteman, Eelco; Wold, Agnes; Wierenga, Eddy A.; Kapsenberg, Martien L.

    2004-01-01

    Dendritic cells (DC) are the main orchestrators of specific immune responses. Depending on microbial information they encounter in peripheral tissues, they promote the development of Th1, Th2 or unpolarized Th cell responses. In this study we have investigated the immunomodulatory effect of

  15. Mycobacterium tuberculosislpdC, Rv0462, induces dendritic cell maturation and Th1 polarization

    Energy Technology Data Exchange (ETDEWEB)

    Heo, Deok Rim [Department of Microbiology and Immunology, School of Medicine, Pusan National University, Beom-eo Ri, Mulgum Eop, Yangsan, Gyeongsangnam-do 626-770 (Korea, Republic of); Shin, Sung Jae; Kim, Woo Sik [Department of Microbiology, College of Medicine, Chungnam National University, Munwha-Dong, Jung-Ku, Daejeon 301-747 (Korea, Republic of); Noh, Kyung Tae; Park, Jin Wook; Son, Kwang Hee [Department of Microbiology and Immunology, School of Medicine, Pusan National University, Beom-eo Ri, Mulgum Eop, Yangsan, Gyeongsangnam-do 626-770 (Korea, Republic of); Park, Won Sun [Department of Physiology, Kangwon National University, School of Medicine, Chuncheon 200-701 (Korea, Republic of); Lee, Min-Goo [Department of Physiology, Korea University, College of Medicine, Anam-dong, Sungbuk-Gu, Seoul 136-705 (Korea, Republic of); Kim, Daejin [Department of Anatomy, Chung-Ang University, College of Medicine, 221 Heuksuk-Dong, Dongjak-Ku, Seoul 156-756 (Korea, Republic of); Shin, Yong Kyoo [Department of Pharmacology, Chung-Ang University, College of Medicine, 221 Heuksuk-Dong, Dongjak-Ku, Seoul 156-756 (Korea, Republic of); Jung, In Duk, E-mail: jungid@pusan.ac.kr [Department of Microbiology and Immunology, School of Medicine, Pusan National University, Beom-eo Ri, Mulgum Eop, Yangsan, Gyeongsangnam-do 626-770 (Korea, Republic of); Research Institute of Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Beom-eo Ri, Mulgum Eop, Yangsan, Gyeongsangnam-do 626-770 (Korea, Republic of); Park, Yeong-Min, E-mail: immunpym@pusan.ac.kr [Department of Microbiology and Immunology, School of Medicine, Pusan National University, Beom-eo Ri, Mulgum Eop, Yangsan, Gyeongsangnam-do 626-770 (Korea, Republic of); Research Institute of Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Beom-eo Ri, Mulgum Eop, Yangsan, Gyeongsangnam-do 626-770 (Korea, Republic of)

    2011-08-05

    Highlights: {yields} Treatment with Rv0462 induces the expression of surface molecules and the production of cytokines in DCs. {yields} Rv0462 induces the activation of MAPKs. {yields} Rv0462-treated DCs enhances the proliferation of CD4{sup +} T cells. -- Abstract: Mycobacterium tuberculosis, the etiological factor of pulmonary tuberculosis, causes significant morbidity and mortality worldwide. Activation of host immune responses for containment of mycobacterial infections involves participation of innate immune cells, such as dendritic cells (DCs). In this study, we demonstrated that the gene encoding lipoamide dehydrogenase C (lpdC) from M. tuberculosis, Rv0462, induce maturation and activation of DCs involved in the MAPKs signaling pathway. Moreover, Rv0462-treated DCs activated naive T cells, polarized CD4{sup +} and CD8{sup +} T cells to secrete IFN-{gamma} in syngeneic mixed lymphocyte reactions, which would be expected to contribute to Th1 polarization of the immune response. Our results suggest that Rv0462 can contribute to the innate and adaptive immune responses during tuberculosis infection, and thus modulate the clinical course of tuberculosis.

  16. Recent progress in understanding host immune response to Avian Coccidiosis: Th1 and Th17 responses

    Science.gov (United States)

    Host-pathogen interaction leading to protection against coccidiosis is complex, involving many aspects of innate and adaptive immunity to intracellular parasites. The etiologic agent of avian coccidiosis is Eimeria, a genus of eukaryotic obligate intracellular parasites belonging to the phylum Apico...

  17. Intestinal immune response to chicken Coccidiosis in the context of Th1 and Th17 response

    Science.gov (United States)

    Coccidiosis is one of the most economically important diseases of the chickens caused by several different Eimeria spp. The primary target tissue of Eimeria parasites is the intestinal mucosa and coccidiosis infection destroys intestinal epithelium resulting in nutrient malabsorption, body weight lo...

  18. Response distortion in personality measurement: born to deceive, yet capable of providing valid self-assessments?

    Directory of Open Access Journals (Sweden)

    STEPHAN DILCHERT

    2006-09-01

    Full Text Available This introductory article to the special issue of Psychology Science devoted to the subject of “Considering Response Distortion in Personality Measurement for Industrial, Work and Organizational Psychology Research and Practice” presents an overview of the issues of response distortion in personality measurement. It also provides a summary of the other articles published as part of this special issue addressing social desirability, impression management, self-presentation, response distortion, and faking in personality measurement in industrial, work, and organizational settings.

  19. Selective Enhancement of Systemic Th1 Immunity in Immunologically Immature Rats with an Orally Administered Bacterial Extract

    OpenAIRE

    Bowman, L. M.; Holt, P. G.

    2001-01-01

    Infant rats primed during the first week of life with soluble antigen displayed adult-equivalent levels of T-helper 2 (Th2)-dependent immunological memory development as revealed by production of secondary immunoglobulin G1 (IgG1) antibody responses to subsequent challenge, but in contrast to adults failed to prime for Th1-dependent IgG2b responses. We demonstrate that this Th2 bias in immune function can be redressed by oral administration to neonates of a bacterial extract (Broncho-Vaxom OM...

  20. Th1-Th17 cells mediate protective adaptive immunity against Staphylococcus aureus and Candida albicans infection in mice.

    Directory of Open Access Journals (Sweden)

    Lin Lin

    2009-12-01

    Full Text Available We sought to define protective mechanisms of immunity to Staphylococcus aureus and Candida albicans bloodstream infections in mice immunized with the recombinant N-terminus of Als3p (rAls3p-N vaccine plus aluminum hydroxide (Al(OH(3 adjuvant, or adjuvant controls. Deficiency of IFN-gamma but not IL-17A enhanced susceptibility of control mice to both infections. However, vaccine-induced protective immunity against both infections required CD4+ T-cell-derived IFN-gamma and IL-17A, and functional phagocytic effectors. Vaccination primed Th1, Th17, and Th1/17 lymphocytes, which produced pro-inflammatory cytokines that enhanced phagocytic killing of both organisms. Vaccinated, infected mice had increased IFN-gamma, IL-17, and KC, increased neutrophil influx, and decreased organism burden in tissues. In summary, rAls3p-N vaccination induced a Th1/Th17 response, resulting in recruitment and activation of phagocytes at sites of infection, and more effective clearance of S. aureus and C. albicans from tissues. Thus, vaccine-mediated adaptive immunity can protect against both infections by targeting microbes for destruction by innate effectors.

  1. Th1-biased immunomodulation and therapeutic potential of Artemisia annua in murine visceral leishmaniasis.

    Directory of Open Access Journals (Sweden)

    Mohammad Islamuddin

    2015-01-01

    Full Text Available In the absence of vaccines and limitations of currently available chemotherapy, development of safe and efficacious drugs is urgently needed for visceral leishmaniasis (VL that is fatal, if left untreated. Earlier we reported in vitro apoptotic antileishmanial activity of n-hexane fractions of Artemisia annua leaves (AAL and seeds (AAS against Leishmania donovani. In the present study, we investigated the immunostimulatory and therapeutic efficacy of AAL and AAS.Ten-weeks post infection, BALB/c mice were orally administered AAL and AAS for ten consecutive days. Significant reduction in hepatic (86.67% and 89.12% and splenic (95.45% and 95.84% parasite burden with decrease in spleen weight was observed. AAL and AAS treated mice induced the strongest DTH response, as well as three-fold decrease in IgG1 and two-fold increase in IgG2a levels, as compared to infected controls. Cytometric bead array further affirmed the elicitation of Th1 immune response as indicated by increased levels of IFN-γ, and low levels of Th2 cytokines (IL-4 and IL-10 in serum as well as in culture supernatant of lymphocytes from treated mice. Lymphoproliferative response, IFN-γ producing CD4+ and CD8+ T lymphocytes and nitrite levels were significantly enhanced upon antigen recall in vitro. The co-expression of CD80 and CD86 on macrophages was significantly augmented. CD8+ T cells exhibited CD62Llow and CD44hi phenotype, signifying induction of immunological memory in AAL and AAS treated groups. Serum enzyme markers were in the normal range indicating inertness against nephro- and hepato-toxicity.Our results establish the two-prong antileishmanial efficacy of AAL and AAS for cure against L. donovani that is dependent on both the direct leishmanicidal action as well as switching-on of Th1-biased protective cell-mediated immunity with generation of memory. AAL and AAS could represent adjunct therapies for the treatment of leishmaniasis, either alone or in combination with

  2. Market and policy barriers for demand response providing ancillary services in U.S. markets

    Energy Technology Data Exchange (ETDEWEB)

    Cappers, Peter [Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); MacDonald, Jason [Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); Goldman, Charles [Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

    2013-03-01

    This study provides an examination of various market and policy barriers to demand response providing ancillary services in both ISO/RTO and non-ISO/RTO regions, especially at the program provider level. It is useful to classify barriers in order to create a holistic understanding and identify parties that could be responsible for their removal. This study develops a typology of barriers focusing on smaller customers that must rely on a program provider (i.e., electric investor owned utility or IOU, ARC) to create an aggregated DR resource in order to bring ancillary services to the balancing authority. The barriers were identified through examinations of regulatory structures, market environments, and product offerings; and discussions with industry stakeholders and regulators. In order to help illustrate the differences in barriers among various wholesale market designs and their constituent retail environments, four regions were chosen to use as case studies: Colorado, Texas, Wisconsin, and New Jersey.

  3. Th1 Cytokine-Secreting Recombinant Mycobacterium bovis Bacillus Calmette-Guérin and Prospective Use in Immunotherapy of Bladder Cancer

    Directory of Open Access Journals (Sweden)

    Yi Luo

    2011-01-01

    Full Text Available Intravesical instillation of Mycobacterium bovis bacillus Calmette-Guérin (BCG has been used for treating bladder cancer for 3 decades. However, BCG therapy is ineffective in approximately 30–40% of cases. Since evidence supports the T helper type 1 (Th1 response to be essential in BCG-induced tumor destruction, studies have focused on enhancing BCG induction of Th1 immune responses. Although BCG in combination with Th1 cytokines (e.g., interferon-α has demonstrated improved efficacy, combination therapy requires multiple applications and a large quantity of cytokines. On the other hand, genetic manipulation of BCG to secrete Th1 cytokines continues to be pursued with considerable interest. To date, a number of recombinant BCG (rBCG strains capable of secreting functional Th1 cytokines have been developed and demonstrated to be superior to BCG. This paper discusses current rBCG research, concerns, and future directions with an intention to inspire the development of this very promising immunotherapeutic modality for bladder cancer.

  4. Comparison of Th1- and Th2-associated immune reactivities stimulated by single versus multiple vaccination of mice with irradiated Schistosoma mansoni cercariae

    Energy Technology Data Exchange (ETDEWEB)

    Caulada-Benedetti, Z.; Al-Zamel, F.; Sher, A.; James, S. (NIAID, Bethesda, MD (USA))

    1991-03-01

    Mice immunized against Schistosoma mansoni by a single percutaneous exposure to radiation-attenuated parasite larvae demonstrate partial resistance to challenge infection that has been shown to correlate with development of cell-mediated immunity, whereas mice hyperimmunized by multiple exposure to attenuated larvae produce antibodies capable of transferring partial protection to naive recipients. Measurement of Ag-specific lymphokine responses in these animals suggested that the difference in resistance mechanisms may be due to the differential induction of Th subset response by the two immunization protocols. Thus, upon Ag stimulation, singly immunized mice predominantly demonstrated responses associated with Th1 reactivity, including IL-2 and IFN-gamma production, whereas multiply immunized animals showed increased IL-5, IL-4, and IgG1 antibody production associated with enhanced Th2 response. These responses demonstrated some degree of organ compartmentalization, with splenocytes demonstrating higher Th1-related lymphokine production and cells from draining lymph nodes showing stronger proliferation and Th2 type reactivity. However, hyperimmunized mice also continued to demonstrate substantial Th1-associated immune reactivity. Moreover, in vivo Ag challenge elicited activated larvacidal macrophages in hyperimmunized animals. These observations indicate that protective cell-mediated mechanisms associated with induction of CD4+ Th1 cell reactivity predominate in singly vaccinated mice. Further vaccination stimulates Th2 responses, such as enhanced IgG1 production, that may also contribute to protective immunity.

  5. Providing Reliability Services through Demand Response: A Prelimnary Evaluation of the Demand Response Capabilities of Alcoa Inc.

    Energy Technology Data Exchange (ETDEWEB)

    Starke, Michael R [ORNL; Kirby, Brendan J [ORNL; Kueck, John D [ORNL; Todd, Duane [Alcoa; Caulfield, Michael [Alcoa; Helms, Brian [Alcoa

    2009-02-01

    Demand response is the largest underutilized reliability resource in North America. Historic demand response programs have focused on reducing overall electricity consumption (increasing efficiency) and shaving peaks but have not typically been used for immediate reliability response. Many of these programs have been successful but demand response remains a limited resource. The Federal Energy Regulatory Commission (FERC) report, 'Assessment of Demand Response and Advanced Metering' (FERC 2006) found that only five percent of customers are on some form of demand response program. Collectively they represent an estimated 37,000 MW of response potential. These programs reduce overall energy consumption, lower green house gas emissions by allowing fossil fuel generators to operate at increased efficiency and reduce stress on the power system during periods of peak loading. As the country continues to restructure energy markets with sophisticated marginal cost models that attempt to minimize total energy costs, the ability of demand response to create meaningful shifts in the supply and demand equations is critical to creating a sustainable and balanced economic response to energy issues. Restructured energy market prices are set by the cost of the next incremental unit of energy, so that as additional generation is brought into the market, the cost for the entire market increases. The benefit of demand response is that it reduces overall demand and shifts the entire market to a lower pricing level. This can be very effective in mitigating price volatility or scarcity pricing as the power system responds to changing demand schedules, loss of large generators, or loss of transmission. As a global producer of alumina, primary aluminum, and fabricated aluminum products, Alcoa Inc., has the capability to provide demand response services through its manufacturing facilities and uniquely through its aluminum smelting facilities. For a typical aluminum smelter

  6. Urban Service Providers' Perspectives on School Responses to Gay, Lesbian, and Questioning Students: An Exploratory Study

    Science.gov (United States)

    Varjas, Kris; Graybill, Emily; Mahan, Will; Meyers, Joel; Dew, Brian; Marshall, Megan; Singh, Anneliese; Birckbichler, Lamar

    2007-01-01

    Perspectives regarding bullying of gay, lesbian, and questioning (GLQ) students were obtained from 16 school and community service providers in this exploratory study. Insights were gained regarding in-school responses to homophobic bullying threats beyond traditional punishments (e.g., suspension). Barriers to developing safe schools for GLQ…

  7. Systems analysis of transcriptome data provides new hypotheses about Arabidopsis root response to nitrate treatments

    Directory of Open Access Journals (Sweden)

    Javier eCanales

    2014-02-01

    Full Text Available Nitrogen (N is an essential macronutrient for plant growth and development. Plants adapt to changes in N availability partly by changes in global gene expression. We integrated publicly available root microarray data under contrasting nitrate conditions to identify new genes and functions important for adaptive nitrate responses in Arabidopsis thaliana roots. Overall, more than two thousand genes exhibited changes in expression in response to nitrate treatments in Arabidopsis thaliana root organs. Global regulation of gene expression by nitrate depends largely on the experimental context. However, despite significant differences from experiment to experiment in the identity of regulated genes, there is a robust nitrate response of specific biological functions. Integrative gene network analysis uncovered relationships between nitrate-responsive genes and eleven highly co-expressed gene clusters (modules. Four of these gene network modules have robust nitrate responsive functions such as transport, signaling and metabolism. Network analysis hypothesized G2-like transcription factors are key regulatory factors controlling transport and signaling functions. Our meta-analysis highlights the role of biological processes not studied before in the context of the nitrate response such as root hair development and provides testable hypothesis to advance our understanding of nitrate responses in plants.

  8. Oral administration of synthetic selenium nanoparticles induced robust Th1 cytokine pattern after HBs antigen vaccination in mouse model.

    Science.gov (United States)

    Mahdavi, Mehdi; Mavandadnejad, Faranak; Yazdi, Mohammad H; Faghfuri, Elnaz; Hashemi, Hura; Homayouni-Oreh, Somayeh; Farhoudi, Ramin; Shahverdi, Ahmad R

    Hepatitis B virus (HBV) infection is known as a life-threatening liver infection and leads to chronic liver disease if left untreated. Nevertheless, the prevalence of HBV infection has been reduced by an approved vaccination approach using recombinant Hepatitis B surface Antigen (HBsAg) and Alum, known as the HBV vaccine. Alum can be used as an adjuvant to increase HBsAg immunogenicity as a strong Th2 stimulator. There is a vital need to stimulate Th1 immunity by HBsAg vaccination; however, the present vaccine does not induce a prophylactic immune response in some groups. The main aim of the present study was to induce a Th1 cytokine pattern and stimulate an immune response after HBsAg vaccination. Experimental mice were fed selenium nanoparticles (SeNPs) and were later immunized with 5μg of Hepatitis B Vaccine. After a period of 30 days, the experimental animals were given two booster doses of SeNPs during their vaccination course. Group one, i.e., the control vaccine group, was only administered the HBsAg vaccine. The two treated groups, Groups 2 and 3, were daily fed different doses of SeNPs (100μg and 200μg, respectively) via gavage. Group four was considered the control group and was only given phosphate buffered saline (PBS). Lymphocyte proliferation, IFN-γ and IL-4 levels, total antibody and the isotypes of IgG1, IgG2a, IgG2b, and IgM were measured by Enzyme Linked Immunosorbent Assay (ELISA). The administration of SeNPs and the HBs antigen vaccine affected the lymphocyte proliferation; moreover, the total antibody responses also increased the IFN-γ level and induced a Th1 response. The present study proposed that the administration of SeNPs with a conventional HBs antigen vaccine induces a better immune response with a Th1 bias. Copyright © 2016 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

  9. Dysregulated cytokine expression by CD4+ T cells from post-septic mice modulates both Th1 and Th2-mediated granulomatous lung inflammation.

    Directory of Open Access Journals (Sweden)

    William F Carson

    Full Text Available Previous epidemiological studies in humans and experimental studies in animals indicate that survivors of severe sepsis exhibit deficiencies in the activation and effector function of immune cells. In particular, CD4+ T lymphocytes can exhibit reduced proliferative capacity and improper cytokine responses following sepsis. To further investigate the cell-intrinsic defects of CD4+ T cells following sepsis, splenic CD4+ T cells from sham surgery and post-septic mice were transferred into lymphopenic mice. These recipient mice were then subjected to both TH1-(purified protein derivative and TH2-(Schistosoma mansoni egg antigen driven models of granulomatous lung inflammation. Post-septic CD4+ T cells mediated smaller TH1 and larger TH2 lung granulomas as compared to mice receiving CD4+ T cells from sham surgery donors. However, cytokine production by lymph node cells in antigen restimulation assays indicated increased pan-specific cytokine expression by post-septic CD4+ T cell recipient mice in both TH1 and TH2 granuloma models. These include increased production of T(H2 cytokines in TH1 inflammation, and increased production of T(H1 cytokines in TH2 inflammation. These results suggest that cell-intrinsic defects in CD4+ T cell effector function can have deleterious effects on inflammatory processes post-sepsis, due to a defect in the proper regulation of TH-specific cytokine expression.

  10. Effect of murine exposure to gamma rays on the interplay between Th1 and Th2 lymphocytes

    Science.gov (United States)

    Ghazy, Amany A.; Abu El-Nazar, Salma Y.; Ghoneim, Hossam E.; Taha, Abdul-Rahman M.; Abouelella, Amira M.

    2015-01-01

    Gamma radiation radiotherapy is one of the widely used treatments for cancer. There is an accumulating evidence that adaptive immunity is significantly contributes to the efficacy of radiotherapy. This study is carried out to investigate the effect of gamma rays on the interplay between Th1/Th2 response, splenocyte lymphoproliferative response to polyclonal mitogenic activators and lymphocytic capacity to produce IL-12 and IL-10 in mice. Results showed that exposure of intact spleens to different doses of γ-rays (5, 10, 20 Gy) caused spontaneous and dose-dependent immune stimulation manifested by enhanced cell proliferation and elevated IL-12 production with decreased IL-10 release (i.e., Th1 bias). While exposure of splenocytes suspension to different doses of γ-rays (5, 10, 20 Gy) showed activation in splenocytes stimulated by PWM at 5 Gy then a state of conventional immune suppression that is characterized by being dose-dependent and is manifested by decreased cell proliferation and IL-12 release accompanied by increase in IL-10 production (i.e., Th2 bias). In addition, we investigated the exposure of whole murine bodies to different doses of γ-rays and found that the exposure to low dose γ-rays (0.2 Gy) caused a state of immune stimulation terminated by a remarkable tendency for immune suppression. Exposure to 5 or 10 Gy of γ-rays resulted in a state of immune stimulation (Th1 bias), but exposure to 20 Gy showed a standard state of immune suppression (Th2 bias). The results indicated that apparently we can control the immune response by controlling the dose of γ-rays. PMID:25914644

  11. Effect of murine exposure to gamma rays on the interplay between Th1 and Th2 lymphocytes.

    Science.gov (United States)

    Ghazy, Amany A; Abu El-Nazar, Salma Y; Ghoneim, Hossam E; Taha, Abdul-Rahman M; Abouelella, Amira M

    2015-01-01

    Gamma radiation radiotherapy is one of the widely used treatments for cancer. There is an accumulating evidence that adaptive immunity is significantly contributes to the efficacy of radiotherapy. This study is carried out to investigate the effect of gamma rays on the interplay between Th1/Th2 response, splenocyte lymphoproliferative response to polyclonal mitogenic activators and lymphocytic capacity to produce IL-12 and IL-10 in mice. Results showed that exposure of intact spleens to different doses of γ-rays (5, 10, 20 Gy) caused spontaneous and dose-dependent immune stimulation manifested by enhanced cell proliferation and elevated IL-12 production with decreased IL-10 release (i.e., Th1 bias). While exposure of splenocytes suspension to different doses of γ-rays (5, 10, 20 Gy) showed activation in splenocytes stimulated by PWM at 5 Gy then a state of conventional immune suppression that is characterized by being dose-dependent and is manifested by decreased cell proliferation and IL-12 release accompanied by increase in IL-10 production (i.e., Th2 bias). In addition, we investigated the exposure of whole murine bodies to different doses of γ-rays and found that the exposure to low dose γ-rays (0.2 Gy) caused a state of immune stimulation terminated by a remarkable tendency for immune suppression. Exposure to 5 or 10 Gy of γ-rays resulted in a state of immune stimulation (Th1 bias), but exposure to 20 Gy showed a standard state of immune suppression (Th2 bias). The results indicated that apparently we can control the immune response by controlling the dose of γ-rays.

  12. Thymic irradiation inhibits the rapid recovery of TH1 but not TH2-like functions of CD4+ T cells after total lymphoid irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Bass, H.; Adkins, B.; Strober, S. (Department of Medicine, Stanford University School of Medicine, CA (United States))

    1991-10-15

    Four to six weeks after total lymphoid irradiation (TLI), there is a selective deficit in the CD4+ T cells which secrete IL-2, proliferate in the MLR, and induce GVHD (Th1-like functions). A similar deficit in CD4+ T cells which secrete IL-4 and help antibody responses (Th2-like functions) is not observed. In the present study, shielding of the thymus with lead during TLI increased the Th1-like functions of CD4+ cells. Mice without thymus shields showed a marked selective reduction in the medullary stromal cells identified with the monoclonal antibody, MD1, and the severe reduction was prevented with thymus shields. Thus, shielding the thymus prevents the depletion of thymic medullary stromal cells and allows for a rapid recovery of Th1-like functions in the mouse spleen after TLI. Th2-like functions recover rapidly after TLI whether or not the thymus is irradiated.

  13. Cerebrospinal fluid Th1/Th2 cytokine profiles in children with enterovirus 71-associated meningoencephalitis.

    Science.gov (United States)

    Li, Huajun; Li, Shuxian; Zheng, Jianfeng; Cai, Chunyan; Ye, Bin; Yang, Jun; Chen, Zhimin

    2015-03-01

    Enterovirus 71 (EV71) infection can cause severe neurological complications including meningoencephalitis (ME) in some patients with hand, foot and mouth disease (HFMD). However, to date no studies have reported changes in cytokine concentrations and their correlations with clinical variables in patients with ME following EV71 infection. In this study, responses of Th1/Th2 cytokine, including IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ, in cerebrospinal fluid (CSF) from patients with EV71-related HFMD with ME and patients with febrile convulsions (FC) were analyzed using cytometric bead array technology. It was found that CSF IL-6 and IFN-γ concentrations were significantly higher in patients with EV71-related ME than in those with FC. Additionally, both CSF IL-6 and IFN-γ concentrations were correlated with CSF cytology, fever duration and duration of hospital stay. More interestingly, a positive correlation between CSF IL-6 and IFN-γ concentrations was observed. Finally, receiver operating characteristic analysis revealed that when a cutoff value of 9.40 pg/mL was set for IL-6, the sensitivity and specificity were 84.5% and 85.5%, respectively, for discriminating EV71-related ME from FC. In conclusion, IL-6 and IFN-γ may be associated with EV71-induced neuropathology. © 2015 The Societies and Wiley Publishing Asia Pty Ltd.

  14. Distinct Th1, Th2 and Treg cytokines balance in chronic periapical granulomas and radicular cysts.

    Science.gov (United States)

    Teixeira-Salum, Tatiana Beber; Rodrigues, Denise Bertulucci Rocha; Gervásio, Aurélia M; Souza, Cássio J A; Rodrigues, Virmondes; Loyola, Adriano Motta

    2010-03-01

    Periapical lesions are a host response that involves immune reaction to prevent dissemination of bacteria from an infected root canal. The purpose of this study was to evaluate the levels of nitric oxide (NO), IL-4, TGF-beta, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) in chronic periapical lesions and to determine their possible association with clinical and radiographic parameters. Seventeen human radicular cysts and 30 periapical granulomas were used in this study. Cytokines and NO were assessed by enzyme-linked immunosorbent assay and by the Griess reaction respectively confirmed by immunohistochemical. TNF-alpha and IFN-gamma were detected in 10% of granulomas and in 41.2% and 70% of radicular cysts. IL-4 was reactive in 24% of cysts, and TGF-beta was positive in all samples. Patients with tenderness showed significantly higher levels of IFN-gamma and IL-4 (P radicular cysts has mist Th1 and Th2 inflammatory reaction with the presence of IFN-gamma, TNF-alpha, and IL-4.

  15. [Effect of pulmonary surfactant on Th1/Th2 balance in neonates with respiratory distress syndrome].

    Science.gov (United States)

    Zhai, Shu-Fen; Liu, Cui-Qing; Ping, Li-Li; Tian, Bao-Li

    2012-12-01

    To investigate the effect of pulmonary surfactant (PS) on the Th1/Th2 balance and serum levels of interleukin-4 (IL-4), interferon-γ (IFN-γ) and IgE in neonates with respiratory distress syndrome (RDS). A total of 58 neonates with RDS were divided into control (n=20) and PS treatment groups (n=38). The control group underwent mechanical ventilation and other conventional treatment, while the PS treatment group received with bovine PS treatment within 1 hour of being admitted to the hospital together with mechanical ventilation and other conventional treatment. Enzyme-linked immunosorbent assay was used to measure serum levels of IL-4, IFN-γ and IgE before treatment and 24, 48 and 72 hours after treatment. Simultaneously, arterial blood gas, respiratory system compliance, and other ventilator parameters were recorded. Compared with the control group, the PS treatment group showed significantly shorter duration of mechanical ventilation and oxygen exposure time (Pneonates with RDS, thus inhibiting lung inflammatory response and reducing lung injury.

  16. Anti-asthma effects of synthetic salidroside through regulation of Th1/Th2 balance.

    Science.gov (United States)

    Wang, Jing; Jin, Rong-Guang; Xiao, Lu; Wang, Qiu-Juan; Yan, Tian-Hua

    2014-07-01

    The aim of the study was to investigate the effect and mechanism of action of synthetic salidroside in an ovalbumin (OVA)-induced asthma model in mice. BALB/c mice were sensitized with an intraperitoneal injection of ovalbumin (OVA) to induce a mouse model of asthma in paracmasis. The mice were treated with dexamethasone as the positive control. At the end of the study, respiratory reactivity was detected, the numbers of various kinds of white blood cells in the bronchoalveolar lavage fluid (BALF) were counted, and the levels of IL-4 and INF-γ in BALF were determined. Quantitative PCR was used to detect the mRNA contents of IL-4 and INF-γ in lung tissue. Histologic examination was performed to observe inflammatory cellular infiltration. Salidroside treatment virtually eliminated airway hyper-reactivity, markedly reduced the eosinophil percent, obviously reduced the levels of IL-4 and raised INF-γ in the bronchoalveolar lavage fluid (BALF) compared with the sham-treated group. Quantitative PCR on the mRNA content of IL-4 and INF-γ provided confirmation. Lung histologic observations showed that salidroside reduced inflammation and edema. These effects were equivalent to the effects of dexamethasone. Synthetic salidroside exhibits an anti-asthma effect which is related to the regulation of Th1/Th2 balance. This provides a new possibility for treatment of allergic asthma. Copyright © 2014 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  17. Heart rate responses provide an objective evaluation of human disturbance stimuli in breeding birds.

    Science.gov (United States)

    Ellenberg, Ursula; Mattern, Thomas; Seddon, Philip J

    2013-01-01

    Intuition is a poor guide for evaluating the effects of human disturbance on wildlife. Using the endangered Yellow-eyed penguin, Megadyptes antipodes, as an example, we show that heart rate responses provide an objective tool to evaluate human disturbance stimuli and encourage the wider use of this simple and low-impact approach. Yellow-eyed penguins are a flagship species for New Zealand's wildlife tourism; however, unregulated visitor access has recently been associated with reduced breeding success and lower first year survival. We measured heart rate responses of Yellow-eyed penguins via artificial eggs to evaluate a range of human stimuli regularly occurring at their breeding sites. We found the duration of a stimulus to be the most important factor, with elevated heart rate being sustained while a person remained within sight. Human activity was the next important component; a simulated wildlife photographer, crawling slowly around during his stay, elicited a significantly higher heart rate response than an entirely motionless human spending the same time at the same distance. Stimuli we subjectively might perceive as low impact, such as the careful approach of a 'wildlife photographer', resulted in a stronger response than a routine nest-check that involved lifting a bird up to view nest contents. A single, slow-moving human spending 20 min within 2 m from the nest may provoke a response comparable to that of 10 min handling a bird for logger deployment. To reduce cumulative impact of disturbance, any human presence in the proximity of Yellow-eyed penguins needs to be kept at a minimum. Our results highlight the need for objective quantification of the effects of human disturbance in order to provide a sound basis for guidelines to manage human activity around breeding birds.

  18. Market and Policy Barriers for Demand Response Providing Ancillary Services in U.S. Markets

    Energy Technology Data Exchange (ETDEWEB)

    Cappers, Peter [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); MacDonald, Jason [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Goldman, Charles [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2013-03-01

    In this study, we attempt to provide a comprehensive examination of various market and policy barriers to demand response providing ancillary services in both ISO/RTO and non-ISO/RTO regions, especially at the program provider level. It is useful to classify barriers in order to create a holistic understanding and identify parties that could be responsible for their removal. This study develops a typology of barriers focusing on smaller customers that must rely on a program provider (i.e., electric investor owned utility or IOU, ARC) to create an aggregated DR resource in order to bring ancillary services to the balancing authority.ii The barriers were identified through examinations of regulatory structures, market environments, and product offerings; and discussions with industry stakeholders and regulators. In order to help illustrate the differences in barriers among various wholesale market designs and their constituent retail environments, four regions were chosen to use as case studies: Colorado, Texas, Wisconsin, and New Jersey. We highlight the experience in each area as it relates to the identified barriers.

  19. Use of a Th1 Stimulator Adjuvant for Vaccination against Neospora caninum Infection in the Pregnant Mouse Model.

    Science.gov (United States)

    Monney, Thierry; Grandgirard, Denis; Leib, Stephen L; Hemphill, Andrew

    2013-03-27

    Vertical transmission from an infected cow to its fetus accounts for the vast majority of new Neospora caninum infections in cattle. A vaccine composed of a chimeric antigen named recNcMIC3-1-R, based on predicted immunogenic domains of the two microneme proteins NcMIC1 and NcMIC3, the rhoptry protein NcROP2, and emulsified in saponin adjuvants, significantly reduced the cerebral infection in non-pregnant BALB/c mice. Protection was associated with a mixed Th1/Th2-type cytokine response. However, the same vaccine formulation elicited a Th2-type immune response in pregnant mice and did not prevent vertical transmission or disease, neither in dams nor in offspring mice. In this study, an alternative vaccine formulation containing recNcMIC3-1-R emulsified in Freund's incomplete adjuvant, a stimulator of the cellular immunity, was investigated. No protection against vertical transmission and cerebral infection in the pregnant mice and a very limited protective effect in the non-pregnant mice were observed. The vaccine induced a Th1-type immune response characterized by high IgG2a titres and strong IFN-γ expression, which appeared detrimental to pregnancy.

  20. Use of a Th1 Stimulator Adjuvant for Vaccination against Neospora caninum Infection in the Pregnant Mouse Model

    Directory of Open Access Journals (Sweden)

    Denis Grandgirard

    2013-03-01

    Full Text Available Vertical transmission from an infected cow to its fetus accounts for the vast majority of new Neospora caninum infections in cattle. A vaccine composed of a chimeric antigen named recNcMIC3-1-R, based on predicted immunogenic domains of the two microneme proteins NcMIC1 and NcMIC3, the rhoptry protein NcROP2, and emulsified in saponin adjuvants, significantly reduced the cerebral infection in non-pregnant BALB/c mice. Protection was associated with a mixed Th1/Th2-type cytokine response. However, the same vaccine formulation elicited a Th2-type immune response in pregnant mice and did not prevent vertical transmission or disease, neither in dams nor in offspring mice. In this study, an alternative vaccine formulation containing recNcMIC3-1-R emulsified in Freund’s incomplete adjuvant, a stimulator of the cellular immunity, was investigated. No protection against vertical transmission and cerebral infection in the pregnant mice and a very limited protective effect in the non-pregnant mice were observed. The vaccine induced a Th1-type immune response characterized by high IgG2a titres and strong IFN-γ expression, which appeared detrimental to pregnancy.

  1. CXCL13 and TH1/Th2 cytokines in the serum and cerebrospinal fluid of neurosyphilis patients.

    Science.gov (United States)

    Yan, Yongxing; Wang, Jun; Qu, Bin; Zhang, Yan; Wei, Yingnan; Liu, Huili; Wu, Chunli

    2017-11-01

    Neurosyphilis is a chronic infectious disease with involvement of central nervous system infection by Treponema pallidum. This study was to investigate the contents of B lymphocyte chemokine 1 (BLC-1/chemokine [C-X-C motif] ligand 13), Th1 cytokines (Interleukin [IL]-2, IL-12, and Interferon [IFN]-γ), and Th2 cytokines (IL-6 and IL-10) in serum and cerebrospinal fluid (CSF) of HIV-negative patients with neurosyphilis before and after treatment, aiming to elucidate roles of CXCL13 and Th1/Th2 cytokines in immune response to and pathogenesis of neurosyphilis.Enzyme-linked immunosorbent assay was employed to detect the contents of CXCL13, IL-2, IL-12, IFN-γ, IL-6, and IL-10 in serum and CSF of 47 HIV-negative patients with neurosyphilis, 36 syphilis patients without neurological involvement and 23 controls (noninfectious intracranial disease) before, 3 and 12 months after treatment with high dose penicillin.Results showed that there was no significant difference in blood CXCL13 content among 3 groups (P > .05); CSF CXCL13 content in neurosyphilis patients was significantly higher than in other 2 groups (P  .05). CSF CXCL13 content was positively related with IL-6 and IL-10 content, while negatively related to IL-12 content in neurosyphilis patients. CSF IL-6 content was negatively related with IL-12 content. In neurosyphilis patients, the CSF CXCL13 content reduced significantly at 3 and 12 months (P cytokines are involved in the immune response of neurosyphilis patients. CSF CXCL13 and Th1/Th2 cytokines contents may be used for the diagnosis and evaluation of therapeutic efficacy of neurosyphilis. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

  2. Quantitative Proteomic Analysis Provides Novel Insights into Cold Stress Responses in Petunia Seedlings.

    Science.gov (United States)

    Zhang, Wei; Zhang, Huilin; Ning, Luyun; Li, Bei; Bao, Manzhu

    2016-01-01

    Low temperature is a major adverse environmental factor that impairs petunia growth and development. To better understand the molecular mechanisms of cold stress adaptation of petunia plants, a quantitative proteomic analysis using iTRAQ technology was performed to detect the effects of cold stress on protein expression profiles in petunia seedlings which had been subjected to 2°C for 5 days. Of the 2430 proteins whose levels were quantitated, a total of 117 proteins were discovered to be differentially expressed under low temperature stress in comparison to unstressed controls. As an initial study, 44 proteins including well known and novel cold-responsive proteins were successfully annotated. By integrating the results of two independent Gene Ontology (GO) enrichment analyses, seven common GO terms were found of which "oxidation-reduction process" was the most notable for the cold-responsive proteins. By using the subcellular localization tool Plant-mPLoc predictor, as much as 40.2% of the cold-responsive protein group was found to be located within chloroplasts, suggesting that the chloroplast proteome is particularly affected by cold stress. Gene expression analyses of 11 cold-responsive proteins by real time PCR demonstrated that the mRNA levels were not strongly correlated with the respective protein levels. Further activity assay of anti-oxidative enzymes showed different alterations in cold treated petunia seedlings. Our investigation has highlighted the role of antioxidation mechanisms and also epigenetic factors in the regulation of cold stress responses. Our work has provided novel insights into the plant response to cold stress and should facilitate further studies regarding the molecular mechanisms which determine how plant cells cope with environmental perturbation. The data have been deposited to the ProteomeXchange with identifier PXD002189.

  3. Mathematical modeling provides kinetic details of the human immune response to vaccination

    Directory of Open Access Journals (Sweden)

    Dustin eLe

    2015-01-01

    Full Text Available With major advances in experimental techniques to track antigen-specific immune responses many basic questions on the kinetics of virus-specific immunity in humans remain unanswered. To gain insights into kinetics of T and B cell responses in human volunteers we combine mathematical models and experimental data from recent studies employing vaccines against yellow fever and smallpox. Yellow fever virus-specific CD8 T cell population expanded slowly with the average doubling time of 2 days peaking 2.5 weeks post immunization. Interestingly, we found that the peak of the yellow fever-specific CD8 T cell response is determined by the rate of T cell proliferation and not by the precursor frequency of antigen-specific cells as has been suggested in several studies in mice. We also found that while the frequency of virus-specific T cells increases slowly, the slow increase can still accurately explain clearance of yellow fever virus in the blood. Our additional mathematical model describes well the kinetics of virus-specific antibody-secreting cell and antibody response to vaccinia virus in vaccinated individuals suggesting that most of antibodies in 3 months post immunization are derived from the population of circulating antibody-secreting cells. Taken together, our analysis provides novel insights into mechanisms by which live vaccines induce immunity to viral infections and highlight challenges of applying methods of mathematical modeling to the current, state-of-the-art yet limited immunological data.

  4. Mathematical modeling provides kinetic details of the human immune response to vaccination.

    Science.gov (United States)

    Le, Dustin; Miller, Joseph D; Ganusov, Vitaly V

    2014-01-01

    With major advances in experimental techniques to track antigen-specific immune responses many basic questions on the kinetics of virus-specific immunity in humans remain unanswered. To gain insights into kinetics of T and B cell responses in human volunteers we combined mathematical models and experimental data from recent studies employing vaccines against yellow fever and smallpox. Yellow fever virus-specific CD8 T cell population expanded slowly with the average doubling time of 2 days peaking 2.5 weeks post immunization. Interestingly, we found that the peak of the yellow fever-specific CD8 T cell response was determined by the rate of T cell proliferation and not by the precursor frequency of antigen-specific cells as has been suggested in several studies in mice. We also found that while the frequency of virus-specific T cells increased slowly, the slow increase could still accurately explain clearance of yellow fever virus in the blood. Our additional mathematical model described well the kinetics of virus-specific antibody-secreting cell and antibody response to vaccinia virus in vaccinated individuals suggesting that most of antibodies in 3 months post immunization were derived from the population of circulating antibody-secreting cells. Taken together, our analysis provided novel insights into mechanisms by which live vaccines induce immunity to viral infections and highlighted challenges of applying methods of mathematical modeling to the current, state-of-the-art yet limited immunological data.

  5. Nurse, physician, and consumer role responsibility perceived by health care providers.

    Science.gov (United States)

    Hammond, K; Bandak, A; Williams, M

    1999-01-01

    The article describes a study that addressed perceptions of unilateral and egalitarian role functions for nurses, physicians, and consumers in a long-term, 345-bed psychiatric facility in the western United States. Findings indicated that physicians desired to retain authority for health care decisions and that nurses, social workers, and hospital administrators preferred collaborative practice. Support for shared responsibility increased among psychiatric technicians with years of experience. Experience did not alter the attitudes of physicians, occupational therapists, and recreational therapists for physician dominance. With experience, nurses increased their belief in nurse responsibility. Despite evidence for collaborative decision making, results of this study indicate that attitudes of health care providers may prevent this tenet from being actualized.

  6. Impacts of Providing Inertial Response on Dynamic Loads of Wind Turbine Drivetrains: Preprint

    Energy Technology Data Exchange (ETDEWEB)

    Girsang, I. P.; Dhupia, J.; Singh, M.; Gevorgian, V.; Muljadi, E.; Jonkman, J.

    2014-09-01

    There has been growing demand from the power industry for wind power plants to support power system operations. One such requirement is for wind turbines to provide ancillary services in the form of inertial response. When the grid frequency drops, it is essential for wind turbine generators (WTGs) to inject kinetic energy stored in their inertia into the grid to help arrest the frequency decline. However, the impacts of inertial response on the structural loads of the wind turbine have not been given much attention. To bridge this gap, this paper utilizes a holistic model for both fixed-speed and variable-speed WTGs by integrating the aeroelastic wind turbine model in FAST, developed by the National Renewable Energy Laboratory, with the electromechanical drivetrain model in SimDriveline and SimPowerSystems.

  7. Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling

    Directory of Open Access Journals (Sweden)

    Smeets Ruben L

    2012-03-01

    activation. PMA/CD3 stimulation enhances a Th1-like response in an Lck and PKCθ dependent fashion, whereas PMA/CD28 stimulation results in a Th2-like phenotype independent of the proximal TCR-tyrosine kinase Lck. This approach offers a robust and fast translational in vitro system for skewed T helper cell responses in Jurkat T cells, primary human CD4+ Tcells and in a more complex matrix such as human whole blood.

  8. Social Responsibility and the State's Duty to provide Healthcare: An Islamic Ethico-Legal Perspective.

    Science.gov (United States)

    Padela, Aasim I

    2017-12-01

    The United Nations Educational, Scientific and Cultural Organization's (UNESCO) Declaration on Bioethics and Human Rights asserts that governments are morally obliged to promote health and to provide access to quality healthcare, essential medicines and adequate nutrition and water to all members of society. According to UNESCO, this obligation is grounded in a moral commitment to promoting fundamental human rights and emerges from the principle of social responsibility. Yet in an era of ethical pluralism and contentions over the universality of human rights conventions, the extent to which the UNESCO Declaration can motivate behaviors and policies rests, at least in part, upon accepting the moral arguments it makes. In this essay I reflect on a state's moral obligation to provide healthcare from the perspective of Islamic moral theology and law. I examine how Islamic ethico-legal conceptual analogues for human rights and communal responsibility, ḥuqūq al-'ibād and farḍ al-kifāyah and other related constructs might be used to advance a moral argument for healthcare provision by the state. Moving from theory to application, I next illustrate how notions of human rights and social responsibility were used by Muslim stakeholders to buttress moral arguments to support American healthcare reform. In this way, the paper advance discourses on a universal bioethics and common morality by bringing into view the concordances and discordances between Islamic ethico-legal constructs and moral arguments advanced by transnational health policy advocates. It also provides insight into applied Islamic bioethics by demonstrating how Islamic ethico-legal values might inform the discursive outputs of Muslim organizations. © 2016 John Wiley & Sons Ltd.

  9. File list: NoD.Bld.50.AllAg.Th1_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available NoD.Bld.50.AllAg.Th1_Cells hg19 No description Blood Th1 Cells SRX290670,SRX290664,...5,SRX736616,SRX736618 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/NoD.Bld.50.AllAg.Th1_Cells.bed ...

  10. Anti-inflammatory effects of 27 selected terpenoid compounds tested through modulating Th1/Th2 cytokine secretion profiles using murine primary splenocytes.

    Science.gov (United States)

    Ku, Chi-Mei; Lin, Jin-Yuarn

    2013-11-15

    This study investigated 27 selected terpenoid compounds, including 8 monoterpenoids, 7 sesqui-terpenoids, 3 di-terpenoids, 8 tri-terpenoids, and 1 tetra-terpenoid, for their Th1/Th2 immunomodulatory potential using mouse primary splenocytes. Changes in Th1 cytokines, including interleukin (IL)-2 and interferon (IFN)-γ, and Th2 cytokines, including IL-4, IL-5 and IL-10, secreted by terpenoid-treated splenocytes were measured using the ELISA method. The results showed that triptolide, a diterpenoid, was most cytotoxic, reflecting an IC50 value of 46nM. Eucalyptol, limonene, linalool, thymol, parthenolide, andrographolide, 18β-glycyrrhetinic acid, lupeol, ursolic acid and β-sitosterol showed a strong Th2-inclination and anti-inflammation potential in vitro. In addition, (-)-trans-caryophyllene, oridonin, triptolide, diosgenin, betulinic acid, escin, and β-sitosterol treatments significantly inhibited both IL-2 (Th1) and IL-10 (Th2) cytokine production at the same time, suggesting that these terpenoid compounds have an anti-inflammation potential through the inhibition of T-cell immune responses. Diosgenin treatments significantly increased IFN-γ secretion levels using mouse splenocytes, suggesting that diosgenin may be useful in treating a viral infection through the stimulation of IFN-γ production. Menthone, farnesol and oridonin treatments did not markedly increase IL-10/IL-2 (Th2/Th1) cytokine secretion ratios, suggesting that menthone, farnesol and oridonin may have a relative Th1-inclination property, compared to the other selected terpenoid compounds. The relative Th1-inclination property of menthone, farnesol and oridonin may be applied to improve Th2-skewed allergic diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. T cell clones from Schistosoma haematobium infected and exposed individuals lacking distinct cytokine profiles for Th1/Th2 polarisation

    Directory of Open Access Journals (Sweden)

    Mduluza T

    2001-01-01

    Full Text Available T cell clones were derived from peripheral blood mononuclear cells of Schistosoma haematobium infected and uninfected individuals living in an endemic area. The clones were stimulated with S. haematobium worm and egg antigens and purified protein derivative. Attempts were made to classify the T cell clones according to production of the cytokines IL-4, IL-5 and IFN-gamma. All the T cell clones derived were observed to produce cytokines used as markers for the classification of Th1/Th2 subsets. However, the 'signature' cytokines marking each subset were produced at different levels. The classification depended on the dominating cytokine type, which was having either Th0/1 or Th0/2 subsets. The results indicated that no distinct cytokine profiles for polarisation of Th1/Th2 subsets were detected in these S. haematobium infected humans. The balance in the profiles of cytokines marking each subset were related to infection and re-infection status after treatment with praziquantel. In the present study, as judged by the changes in infection status with time, the T cell responses appeared to be less stable and more dynamic, suggesting that small quantitative changes in the balance of the cytokines response could result in either susceptibility or resistant to S. haematobium infection.

  12. A polysaccharide isolated from Agaricus blazei Murill (ABP-AW1) as a potential Th1 immunity-stimulating adjuvant.

    Science.gov (United States)

    Cui, Liran; Sun, Yongxu; Xu, Hao; Xu, Huiyu; Cong, Huan; Liu, Jicheng

    2013-10-01

    In the present study, a low molecular weight polysaccharide, ABP-AW1, isolated from Agaricus blazei Murill was assessed for its potential adjuvant activity. ABP-AW1 is considered to create a 'depot' of antigen at a subcutaneous injection site. ICR mice were immunized with 100 μg ovalbumin (OVA) alone or with 100 μg OVA formulated in 0.9% saline containing 200 μg aluminum (alum) or ABP-AW1 (50, 100 and 200 μg) on days 1 and 15. Two weeks after the secondary immunization, splenocyte proliferation, the expression of surface markers, cytokine production and the OVA-specific antibody levels in the serum were determined. The OVA/ABP-AW1 vaccine, in comparison with OVA alone, markedly increased the proliferation of splenic lymphocytes and elicited greater antigen-specific CD4+ T cell activation, as determined by splenic CD4+CD69+ T cells and Th1 cytokine interferon (IFN)-γ release. The combination of ABP-AW1 and OVA also enhanced IgG2b antibody responses to OVA. In conclusion, these data indicated that ABP-AW1 significantly enhanced the humoral and cellular immune responses against OVA in the mice, suggesting that ABP-AW1 stimulated Th1-type immunity. We suggest that ABP-AW1 may serve as a new adjuvant.

  13. Ulmus davidiana var. japonica Nakai upregulates eosinophils and suppresses Th1 and Th17 cells in the small intestine.

    Directory of Open Access Journals (Sweden)

    Han-Sung Lee

    Full Text Available The bark of Ulmus davidiana var. japonica Nakai (Ulmaceae has been used in traditional Korean medicine for chronic inflammation in the gastrointestinal tract. Here we investigated the frequency and cytokine profile of the major immune cells in the small intestinal lamina propria (SI LP, spleen, and mesenteric lymph nodes (MLNs of mice treated orally with Ulmus davidiana var. japonica Nakai bark water extract (UDE to address the immunomodulatory role of this herb in intestinal homeostasis. B6 mice were given 5g/kg UDE once daily for 14 days. They were then sacrificed, and cells were isolated from the spleen, MLNs, and SI LP. The proportion of B versus T lymphocytes, CD4(+ versus CD8(+ T lymphocytes, Th1 and Th17 cells, and Foxp3(+ regulatory T cells in the spleen, MLNs, and SI LP were analyzed. The frequency of antigen-presenting cells (APCs, including dendritic cells, macrophages, and eosinophils in the SI LP and the expression of costimulatory molecules on APCs were also evaluated. The numbers and frequencies of Th1 and Th17 cells in the SI LP were significantly reduced in the UDE-treated mice compared with PBS controls. In addition, the proportion of IL-4-producing eosinophils in the SI LP was significantly elevated in the UDE-treated mice compared with controls. Taken together, these data indicate that UDE up-regulates the number and frequency of SI LP eosinophils, which can down-regulate the Th1 and Th17 responses via IL-4 secretion and contribute to intestinal homeostasis.

  14. 41 CFR 102-79.95 - Who is responsible for the costs associated with providing access to antenna sites?

    Science.gov (United States)

    2010-07-01

    ... providing access to antenna sites? The telecommunications service provider is responsible for any reasonable... support of constructing new and improving existing telecommunication infrastructures provided that such installation does not negatively impact on the Government. ...

  15. Improving Providers' Role Definitions to Decrease Overcrowding and Improve In-Hospital Cardiac Arrest Response.

    Science.gov (United States)

    Leary, Marion; Schweickert, William; Neefe, Stacie; Tsypenyuk, Boris; Falk, Scott Austin; Holena, Daniel N

    2016-07-01

    How nontechnical factors such as inadequate role definition and overcrowding affect outcomes of in-hospital cardiac arrest (IHCA) is unknown. Using a bundled intervention, we sought to improve providers' role definitions and decrease overcrowding during IHCA events. To determine if a bundled intervention consisting of a nurse/physician leadership dyad, visual cues for provider roles, and a "role check" would lead to reductions in crowding and improve perceptions of communication and team leadership. Baseline data on the number and type of IHCA providers were collected. Providers were asked to complete a postevent survey rating communication and leadership. A bundled intervention was then introduced. Data were then obtained for the subsequent IHCA events. Twenty ICHA events were captured before and 34 after the intervention. The number of physicians present at pulse checks 2 (median [interquartile range]: 6 [5-8] before vs 5 [3-6] after, P = .02) and 3 (7 [5-9] vs 4 [4-5], P = .004) decreased significantly after the intervention. The overall number of providers at the third pulse check (18 [14-22] before vs 14 [12-16] after, P = .04) also decreased after the intervention. On a 10-point Likert scale, ratings of communication (8 [7-8]) and physician leadership (8 [7-9]) did not differ significantly from before to after the intervention. Both the physician leads (90%) and patients' primary nurses (97%) were able to identify clear nurse leaders. A bundled intervention targeted at improving IHCA response led to a decrease in overcrowding at ICHA events without substantial changes in the perceptions of communication or physician leadership. ©2016 American Association of Critical-Care Nurses.

  16. Differential effects of Th1 versus Th2 cytokines in combination with hypoxia on HIFs and angiogenesis in RA

    Science.gov (United States)

    2012-01-01

    Introduction Hypoxia and T-helper cell 1 (Th1) cytokine-driven inflammation are key features of rheumatoid arthritis (RA) and contribute to disease pathogenesis by promoting angiogenesis. The objective of our study was to characterise the angiogenic gene signature of RA fibroblast-like synoviocytes (FLS) in response to hypoxia, as well as Th1 and T-helper cell 2 (Th2) cytokines, and in particular to dissect out effects of combined hypoxia and cytokines on hypoxia inducible transcription factors (HIFs) and angiogenesis. Methods Human angiogenesis PCR arrays were used to screen cDNA from RA FLS exposed to hypoxia (1% oxygen) or dimethyloxalylglycine, which stabilises HIFs. The involvement of HIF isoforms in generating the angiogenic signature of RA FLS stimulated with hypoxia and/or cytokines was investigated using a DNA-binding assay and RNA interference. The angiogenic potential of conditioned media from hypoxia-treated and/or cytokine-treated RA FLS was measured using an in vitro endothelial-based assay. Results Expression of 12 angiogenic genes was significantly altered in RA FLS exposed to hypoxia, and seven of these were changed by dimethyloxalylglycine, including ephrin A3 (EFNA3), vascular endothelial growth factor (VEGF), adipokines angiopoietin-like (ANGPTL)-4 and leptin. These four proangiogenic genes were dependent on HIF-1 in hypoxia to various degrees: EFNA3 >ANGPTL-4 >VEGF >leptin. The Th1 cytokines TNFα and IL-1β induced HIF-1 but not HIF-2 transcription as well as activity, and this effect was additive with hypoxia. In contrast, Th2 cytokines had no effect on HIFs. IL-1β synergised with hypoxia to upregulate EFNA3 and VEGF in a HIF-1-dependent fashion but, despite strongly inducing HIF-1, TNFα suppressed adipokine expression and had minimal effect on EFNA3. Supernatants from RA FLS subjected to hypoxia and TNFα induced fewer endothelial tubules than those from FLS subjected to TNFα or hypoxia alone, despite high VEGF protein levels. The Th2

  17. NF-kappa B1 is required for optimal CD4+ Th1 cell development and resistance to Leishmania major.

    Science.gov (United States)

    Artis, David; Speirs, Kendra; Joyce, Karen; Goldschmidt, Michael; Caamaño, Jorge; Hunter, Christopher A; Scott, Phillip

    2003-02-15

    The NF-kappaB family of transcription factors regulates the expression of a wide range of immune response genes involved in immunity to pathogens. However, the need for individual family members in regulating innate and adaptive immune responses in vivo has yet to be clearly defined. We investigated the role of NF-kappaB1 in the induction of protective IL-12-dependent Th1 cell responses following infection with the intracellular protozoan parasite Leishmania major. Whereas wild-type C57BL/6 mice controlled parasite replication, NF-kappaB1 knockout (KO) mice were susceptible to infection, developing chronic unresolving lesions associated with persistent parasites. There was a profound defect in Ag-specific CD4(+) T cell proliferation and IFN-gamma production in infected KO mice, although innate responses-including IL-12 production and control of intracellular parasite replication by macrophages-were intact. In vitro polyclonal stimulation of purified naive KO T cells revealed an intrinsic defect in CD4(+) T cell proliferation associated with reduced IL-2 receptor expression, but operating independently of APC function and IL-2 production. Critically, the frequency of proliferating KO CD4(+) T cells secreting IFN-gamma matched that of wild-type cells, suggesting that NF-kappaB1 was not required for efficient transcription of the IFN-gamma gene. Taken together, these results identify a novel role for NF-kappaB1 in CD4(+) T cell proliferation and the development of Th1 cell responses required for protective immunity against intracellular pathogens.

  18. A PC parallel port button box provides millisecond response time accuracy under Linux.

    Science.gov (United States)

    Stewart, Neil

    2006-02-01

    For psychologists, it is sometimes necessary to measure people's reaction times to the nearest millisecond. This article describes how to use the PC parallel port to receive signals from a button box to achieve millisecond response time accuracy. The workings of the parallel port, the corresponding port addresses, and a simple Linux program for controlling the port are described. A test of the speed and reliability of button box signal detection is reported. If the reader is moderately familiar with Linux, this article should provide sufficient instruction for him or her to build and test his or her own parallel port button box. This article also describes how the parallel port could be used to control an external apparatus.

  19. Proteomic analyses provide new insights into the responses of Pinus massoniana seedlings to phosphorus deficiency.

    Science.gov (United States)

    Fan, Fuhua; Ding, Guijie; Wen, Xiaopeng

    2016-02-01

    Phosphorus is an essential macronutrient for plant growth and development. Plants can respond defensively to phosphorus deficiency by modifying their morphology and metabolic pathways via the differential expression of low phosphate responsive genes. To better understand the mechanisms by which the Masson pine (Pinus massoniana) adapts to phosphorus deficiency, we conducted comparative proteomic analysis using an elite line exhibiting high tolerance to phosphorus deficiency. The selected seedlings were treated with 0.5 mM KH2PO4 (control), 0.01 mM KH2PO4 (P1), or 0.06 mM KH2PO4 (P2) for 48 days. Total protein samples were separated via 2DE. A total of 98 differentially expressed proteins, which displayed at least 1.7-fold change expression compared to the control levels (p ≤ 0.05), were identified by MALDI-TOF/TOF MS. These phosphate starvation responsive proteins were implicated in photosynthesis, defense, cellular organization, biosynthesis, energy metabolism, secondary metabolism, signal transduction etc. Therefore, these proteins might play important roles in facilitating internal phosphorus homeostasis. Additionally, the obtained data may be useful for the further characterization of gene function and may provide a foundation for a more comprehensive understanding of the adaptations of the Masson pine to phosphorus-deficient conditions. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. 29 CFR 2.33 - Responsibilities of DOL, DOL social service providers and State and local governments...

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 1 2010-07-01 2010-07-01 true Responsibilities of DOL, DOL social service providers and... Organizations; Protection of Religious Liberty of Department of Labor Social Service Providers and Beneficiaries § 2.33 Responsibilities of DOL, DOL social service providers and State and local governments...

  1. Leprosy As a Complex Infection: Breakdown of the Th1 and Th2 Immune Paradigm in the Immunopathogenesis of the Disease

    Directory of Open Access Journals (Sweden)

    Jorge Rodrigues de Sousa

    2017-11-01

    Full Text Available Leprosy is a chronic infectious disease whose evolution involves complex immune mechanisms of the host that influence the clinical presentation of the disease. For many years, the main interpretation of the host defense response was based on characterization of the established immune paradigm between T helper (Th 1 and Th2 lymphocytes. However, with advances in the knowledge of immunology, new approaches have emerged along with the development of new immunological pathways that have changed the interpretation of the long-established paradigm of the polar forms of the disease, especially with the identification of new subtypes of T lymphocytes such as Th9, Th17, Th22, and Tregs. Thus, this review discusses the role of these new subtypes of T helper lymphocytes and how the development of the immune response of these cells modifies the pattern of the Th1/Th2 response in the immunopathogenesis of leprosy.

  2. Circulating Th17, Th22, and Th1 Cells Are Elevated in the Guillain-Barré Syndrome and Downregulated by IVIg Treatments

    Directory of Open Access Journals (Sweden)

    Shujuan Li

    2014-01-01

    Full Text Available The Guillain-Barré syndrome (GBS is considered a T helper 1 (Th1 cells-mediated acute inflammatory peripheral neuropathy. However, some changes in GBS could not be explained completely by Th1 cells pathogenic role. Recently, Th17 cells have been identified and can mediate tissue inflammation and autoimmune response. Therefore, a study on the role of Th17 and Th22 cells and their cytokines in GBS is necessary for exploring the pathogenesis of GBS. Here, we detected the frequency of Th1, Th17, and Th22 cells by using 4-color flow cytometry and we detected the plasma levels of IL-17 and IL-22 by ELISA in GBS patients, relapsing-remitting multiple sclerosis patients at the acute phase of relapse, viral encephalitis or meningitis patients and healthy controls. Our data showed that the frequency of circulating Th1, Th17, and Th22 cells was significantly increased in GBS patients. The plasma levels of IL-17 and IL-22 in GBS and relapsing-remitting multiple sclerosis at the acute phase of relapse were also markedly elevated. Enhanced circulating Th22 cells were correlated with GBS severity. Intravenous immunoglobulin therapy downregulated Th17, and Th22 cells and the plasma levels of IL-17 and IL-22 in GBS patients. Th17 and Th22 cells may be involved in the pathogenesis of GBS, and intravenous immunoglobulin mediates therapeutic effects by downregulating these cells and their cytokines.

  3. Intercellular adhesion molecule-1/LFA-1 ligation favors human Th1 development

    NARCIS (Netherlands)

    Smits, Hermelijn H.; de Jong, Esther C.; Schuitemaker, Joost H. N.; Geijtenbeek, Theo B. H.; van Kooyk, Yvette; Kapsenberg, Martien L.; Wierenga, Eddy A.

    2002-01-01

    Th cell polarization toward Th1 or Th2 cells is strongly driven by exogenous cytokines, in particular IL-12 or IL-4, if present during activation by Ag-presenting dendritic cells (DC). However, additional Th cell polarizing mechanisms are induced by the ligation of cell surface molecules on DC and

  4. Immunomodulatory Effects of Taiwanese Neolitsea Species on Th1 and Th2 Functionality

    Science.gov (United States)

    Chen, Ih-Sheng

    2017-01-01

    Neolitsea species, medicinal plants belonging to Lauraceae, contain rich alkaloids, steroids, sesquiterpenoids, and triterpenoids which possess antimicrobial, antioxidant, and anti-inflammatory bioactivities. However, species differences in the immunomodulatory effects and evidence pertaining to the effects of Neolitsea species on adaptive immunity are scarce. This study aimed to evaluate the immunomodulatory properties of ten Taiwanese Neolitsea plants on T helper (Th) cell functionality, especially Th1 and Th2. Most of the 29 crude extracts of Neolitsea were not toxic to splenocytes, except N. buisanensis roots. N. aciculata and N. villosa leaf extracts possessed differential immunomodulatory effects on Th1/Th2 balance. N. aciculata var. variabillima and N. hiiranensis leaf extracts attenuated both Th1 and Th2 cytokines while N. konishii dramatically suppressed IFN-γ production. As N. aciculata var. variabillima and N. konishii leaf extracts significantly attenuated Th1 functionality, we further evaluated their effects on CD4 cells under CD3/CD28 stimulation. N. aciculata var. variabillima significantly suppressed IFN-γ, IL-10, and IL-17, demonstrating the broad suppressive effects on T helper cells; N. konishii significantly suppressed IFN-γ and IL-10 production, while the production of IL-17 was not altered. Collectively, these data demonstrated that leaf extracts of Taiwanese Neolitsea species contain phytochemicals with potentials to be developed as selective immunomodulators. PMID:28781969

  5. Impaired Th1 cytokine production in spondyloarthropathy is restored by anti-TNFalpha

    NARCIS (Netherlands)

    Baeten, D.; van Damme, N.; van den Bosch, F.; Kruithof, E.; de Vos, M.; Mielants, H.; Veys, E. M.; de Keyser, F.

    2001-01-01

    OBJECTIVES: To evaluate the effect of anti-TNFalpha on the Th1 and Th2 cytokines in patients with spondyloarthropathy (SpA). METHODS: Peripheral blood mononuclear cells (PBMC) were obtained from 20 patients with active SpA treated with infliximab (5 mg/kg). For comparison, PBMC were also obtained

  6. Modulation of immune cells and Th1/Th2 cytokines in insulin-treated ...

    African Journals Online (AJOL)

    Modulation of immune cells and Th1/Th2 cytokines in insulin-treated type 2 diabetes mellitus. Magloire Pandoua Nekoua1, Rufine Fachinan1, Amidou K Atchamou1, Odilon Nouatin2,. Daniel Amoussou-Guenou3, Marcellin K Amoussou-Guenou4, Kabirou Moutairou1, Akadiri Yessoufou1. 1. Laboratory of Cell Biology and ...

  7. Preliminary Location Accuracy Assessments of 3rd Satellite of TH-1

    Directory of Open Access Journals (Sweden)

    WANG Renxiang

    2016-10-01

    Full Text Available The TH-1 satellite is the first stereo mapping transmission satellite in China, and the primary mission goal of the satellite is for topographic mapping at 1:50 000 scale and high-accuracy location without Ground Control Points (GCPs. 1st, 2nd satellites of TH-1 were launched on August 24, 2010, May 6, 2012, and 3rd satellite was launched on October 26, 2015. Now, three satellites of TH-1 are well operating on its orbit. After evaluation, the location accuracy of 1st satellite without GCPs is 10.3 m/5.7 m (horizontal accuracy/vertical elevation accuracy, and the location accuracy of 2nd is equivalent with 1st satellite. In this paper, the system overview of TH-1 and the key technical in ground image processing are introduced. Then, the preliminary location accuracy of 3rd is assessed. The results are shown using three routes images:the location accuracy of 3rd is higher than 2nd, and can realize high accuracy location without GCPs, in which the horizontal accuracy is 7.2 m, and the vertical elevation accuracy is 2.6 m.

  8. Transcriptome analysis of Crossostephium chinensis provides insight into the molecular basis of salinity stress responses.

    Directory of Open Access Journals (Sweden)

    Haiyan Yang

    Full Text Available Soil salinization is becoming a limitation to the utilization of ornamental plants worldwide. Crossostephium chinensis (Linnaeus Makino is often cultivated along the southeast coast of China for its desirable ornamental qualities and high salt tolerance. However, little is known about the genomic background of the salt tolerance mechanism in C. chinensis. In the present study, we used Illumina paired-end sequencing to systematically investigate leaf transcriptomes derived from C. chinensis seedlings grown under normal conditions and under salt stress. A total of 105,473,004 bp of reads were assembled into 163,046 unigenes, of which 65,839 (40.38% of the total and 54,342 (33.32% of the total were aligned in Swiss-Prot and Nr protein, respectively. A total of 11,331 (6.95% differentially expressed genes (DEGs were identified among three comparisons, including 2,239 in 'ST3 vs ST0', 5,880 in 'ST9 vs ST3' and 9,718 in 'ST9 vs ST0', and they were generally classified into 26 Gene Ontology terms and 58 Kyoto Encyclopedia of Genes and Genomes (KEGG pathway terms. Many genes encoding important transcription factors (e.g., WRKY, MYB, and AP2/EREBP and proteins involved in starch and sucrose metabolism, arginine and proline metabolism, plant hormone signal transduction, amino acid biosynthesis, plant-pathogen interactions and carbohydrate metabolism, among others, were substantially up-regulated under salt stress. These genes represent important candidates for studying the salt-response mechanism and molecular biology of C. chinensis and its relatives. Our findings provide a genomic sequence resource for functional genetic assignments in C. chinensis. These transcriptome datasets will help elucidate the molecular mechanisms responsible for salt-stress tolerance in C. chinensis and facilitate the breeding of new stress-tolerant cultivars for high-saline areas using this valuable genetic resource.

  9. IFN Regulatory Factor 3 Balances Th1 and T Follicular Helper Immunity during Nonlethal Blood-Stage Plasmodium Infection.

    Science.gov (United States)

    James, Kylie R; Soon, Megan S F; Sebina, Ismail; Fernandez-Ruiz, Daniel; Davey, Gayle; Liligeto, Urijah N; Nair, Arya Sheela; Fogg, Lily G; Edwards, Chelsea L; Best, Shannon E; Lansink, Lianne I M; Schroder, Kate; Wilson, Jane A C; Austin, Rebecca; Suhrbier, Andreas; Lane, Steven W; Hill, Geoffrey R; Engwerda, Christian R; Heath, William R; Haque, Ashraful

    2018-01-10

    Differentiation of CD4+ Th cells is critical for immunity to malaria. Several innate immune signaling pathways have been implicated in the detection of blood-stage Plasmodium parasites, yet their influence over Th cell immunity remains unclear. In this study, we used Plasmodium-reactive TCR transgenic CD4+ T cells, termed PbTII cells, during nonlethal P. chabaudi chabaudi AS and P. yoelii 17XNL infection in mice, to examine Th cell development in vivo. We found no role for caspase1/11, stimulator of IFN genes, or mitochondrial antiviral-signaling protein, and only modest roles for MyD88 and TRIF-dependent signaling in controlling PbTII cell expansion. In contrast, IFN regulatory factor 3 (IRF3) was important for supporting PbTII expansion, promoting Th1 over T follicular helper (Tfh) differentiation, and controlling parasites during the first week of infection. IRF3 was not required for early priming by conventional dendritic cells, but was essential for promoting CXCL9 and MHC class II expression by inflammatory monocytes that supported PbTII responses in the spleen. Thereafter, IRF3-deficiency boosted Tfh responses, germinal center B cell and memory B cell development, parasite-specific Ab production, and resolution of infection. We also noted a B cell-intrinsic role for IRF3 in regulating humoral immune responses. Thus, we revealed roles for IRF3 in balancing Th1- and Tfh-dependent immunity during nonlethal infection with blood-stage Plasmodium parasites. Copyright © 2018 by The American Association of Immunologists, Inc.

  10. Transgenerational endpoints provide increased sensitivity and insight into multigenerational responses of Lymnaea stagnalis exposed to cadmium.

    Science.gov (United States)

    Reátegui-Zirena, Evelyn G; Fidder, Bridgette N; Olson, Adric D; Dawson, Daniel E; Bilbo, Thomas R; Salice, Christopher J

    2017-05-01

    Ecotoxicology provides data to inform environmental management. Many testing protocols do not consider offspring fitness and toxicant sensitivity. Cadmium (Cd) is a well-studied and ubiquitous toxicant but little is known about the effects on offspring of exposed parents (transgenerational effects). This study had three objectives: to identify endpoints related to offspring performance; to determine whether parental effects would manifest as a change in Cd tolerance in offspring and how parental exposure duration influenced the manifestation of parental effects. Adult snails were exposed to Cd 0, 25, 50, 100, 200 and 400 μg Cd/L for eight weeks. There were effects on adult endpoints (e.g., growth, reproduction) but only at the highest concentrations (>100 μg/L). Alternatively, we observed significant transgenerational effects at all Cd concentrations. Surprisingly, we found increased Cd tolerance in hatchlings from all parental Cd exposure concentrations even though eggs and hatchlings were in Cd-free conditions for 6 weeks. Explicit consideration of offspring performance adds value to current toxicity testing protocols. Parental exposure duration has important implications for offspring effects and that contaminant concentrations that are not directly toxic to parents can cause transgenerational changes in resistance that have significant implications for toxicity testing and adaptive responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Airway hyper-responsiveness to mannitol provides a good evaluation of atopy in childhood asthma.

    Science.gov (United States)

    Attanasi, M; Rapino, D; Marcovecchio, M L; Consilvio, N P; Scaparrotta, A; Cingolani, A; Di Pillo, S; Chiarelli, F

    2015-07-01

    The relationship between airway hyper-responsiveness (AHR) and atopy has been previously investigated, but there are still some issues to be clarified. The aim of this study was to assess the link between AHR and mannitol and atopy in asthmatic children. We evaluated 44 children with asthma, aged 6-16 years of age, using skin prick tests (SPTs), serum total and specific immunoglobulin E (IgE) levels and the mannitol challenge test (MCT). We found a good correlation between AHR to mannitol and specific IgE against Dermatophagoides pteronissinus (r = -0.66, p mannitol and serum total IgE (r = -0.30; p = 0.03), the sum of specific IgE to aeroallergens (r = -0.37, p = 0.01) and the number of positive SPTs (r = -0.31, p = 0.02). Measuring AHR with MCT might provide an accurate evaluation of the degree of atopy in children. The patients with a higher degree of atopy were significantly more reactive to mannitol. In clinical practice, these results indicate that children with asthma who are more atopic may require more intensive treatment strategies to reduce AHR. ©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  12. Transcriptional profiling reveals molecular signatures associated with HIV permissiveness in Th1Th17 cells and identifies peroxisome proliferator-activated receptor gamma as an intrinsic negative regulator of viral replication.

    Science.gov (United States)

    Bernier, Annie; Cleret-Buhot, Aurélie; Zhang, Yuwei; Goulet, Jean-Philippe; Monteiro, Patricia; Gosselin, Annie; DaFonseca, Sandrina; Wacleche, Vanessa Sue; Jenabian, Mohammad-Ali; Routy, Jean-Pierre; Tremblay, Cécile; Ancuta, Petronela

    2013-12-21

    We previously demonstrated that primary Th1Th17 cells are highly permissive to HIV-1, whereas Th1 cells are relatively resistant. Molecular mechanisms underlying these differences remain unknown. Exposure to replication competent and single-round VSV-G pseudotyped HIV strains provide evidence that superior HIV replication in Th1Th17 vs. Th1 cells was regulated by mechanisms located at entry and post-entry levels. Genome-wide transcriptional profiling identified transcripts upregulated (n = 264) and downregulated (n = 235) in Th1Th17 vs. Th1 cells (p-value TNFSF13B, TNFSF25, PTPN13, MAP3K4, LTB, CTSH), transcription (PPARγ, RUNX1, ATF5, ARNTL), apoptosis (FASLG), and HIV infection (CXCR6, FURIN). Differential expression of CXCR6, PPARγ, ARNTL, PTPN13, MAP3K4, CTSH, SERPINB6, PTK2, and ISG20 was validated by RT-PCR, flow cytometry and/or confocal microscopy. The nuclear receptor PPARγ was preferentially expressed by Th1Th17 cells. PPARγ RNA interference significantly increased HIV replication at levels post-entry and prior HIV-DNA integration. Finally, the activation of PPARγ pathway via the agonist Rosiglitazone induced the nuclear translocation of PPARγ and a robust inhibition of viral replication. Thus, transcriptional profiling in Th1Th17 vs. Th1 cells demonstrated that HIV permissiveness is associated with a superior state of cellular activation and limited antiviral properties and identified PPARγ as an intrinsic negative regulator of viral replication. Therefore, triggering PPARγ pathway via non-toxic agonists may contribute to limiting covert HIV replication and disease progression during antiretroviral treatment.

  13. Provider-patient in-office discussions of response to hepatitis C antiviral therapy and impact on patient comprehension.

    Science.gov (United States)

    Hamilton, Heidi E; Nelson, Meaghan; Martin, Paul; Cotler, Scott J

    2006-04-01

    Providers need to communicate projected response rates effectively to enable patients with hepatitis C virus to make informed decisions about therapy. This study used interactional sociolinguistics (1) to evaluate how gastroenterologists and allied health professionals communicate information regarding response rates to antiviral therapy, (2) to determine how these discussions relate to where the patient is in the continuum of evaluation and treatment, (3) to assess whether patients were aligned with providers in their perceptions of response rates after office visits, and (4) to identify factors that improve provider-patient alignment. Gastroenterologists, allied health professionals, and patients with hepatitis C virus were videotaped and audiotaped during regularly scheduled visits. Postvisit interviews were conducted separately with patients and providers. Visits and postvisits were transcribed and analyzed using validated sociolinguistic techniques. The phase of hepatitis C virus treatment shaped the benchmarks of response talk, although across the treatment continuum providers overwhelmingly made strategic use of positive statistics, providing motivation. In postvisit interviews, 55% of providers and patients were aligned on response rates. Patients with a favorable outcome and patients who asked response-related questions in the visit were more likely to be aligned with providers. Areas identified for improvement included the tendency to discuss response rates before an individualized assessment could be made, balancing motivation and accuracy, and assessing the patient's perspective before delivering any bad news, if necessary. Sociolinguistic analysis provides a powerful tool to evaluate provider-patient interactions and to identify ways to improve in-office communication regarding antiviral therapy.

  14. Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway.

    Science.gov (United States)

    Wu, Xin; Dou, Yannong; Yang, Yan; Bian, Difei; Luo, Jinque; Tong, Bei; Xia, Yufeng; Dai, Yue

    2015-08-15

    Arctigenin, the main effective constituent of Arctium lappa L. fruit, has previously been proven to dramatically attenuate dextran sulfate sodium (DSS)-induced colitis in mice, a frequently used animal model of inflammatory bowel disease (IBD). As Th1 and Th17 cells play a crucial role in the pathogenesis of IBD, the present study addressed whether and how arctigenin exerted anti-colitis efficacy by interfering with the differentiation and activation of Th1/Th17 cells. In vitro, arctigenin was shown to markedly inhibit the differentiation of Th17 cells from naïve T cells, and moderately inhibit the differentiation of Th1 cells, which was accompanied by lowered phosphorylation of STAT3 and STAT4, respectively. In contrast, arctigenin was lack of marked effect on the differentiation of either Th2 or regulatory T cells. Furthermore, arctigenin was shown to suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway in T cells as demonstrated by down-regulated phosphorylation of the downstream target genes p70S6K and RPS6, and it functioned independent of two well-known upstream kinases PI3K/AKT and ERK. Arctigenin was also able to inhibit the activity of mTORC1 by dissociating raptor from mTOR. Interestingly, the inhibitory effect of arctigenin on T cell differentiation disappeared under a status of mTORC1 overactivation via knockdown of tuberous sclerosis complex 2 (TSC2, a negative regulator of mTORC1) or pretreatment of leucine (an agonist of mTOR). In DSS-induced mice, the inhibition of Th1/Th17 responses and anti-colitis effect of arctigenin were abrogated by leucine treatment. In conclusion, arctigenin ameliorates colitis through down-regulating the differentiation of Th1 and Th17 cells via mTORC1 pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. 41 CFR 102-77.25 - Do Federal agencies have responsibilities to provide national visibility for Art-in-Architecture?

    Science.gov (United States)

    2010-07-01

    ... responsibilities to provide national visibility for Art-in-Architecture? 102-77.25 Section 102-77.25 Public... MANAGEMENT REGULATION REAL PROPERTY 77-ART-IN-ARCHITECTURE Art-in-Architecture § 102-77.25 Do Federal agencies have responsibilities to provide national visibility for Art-in-Architecture? Yes, Federal...

  16. DNA immunization against amyloid beta 42 has high potential as safe therapy for Alzheimer's disease as it diminishes antigen-specific Th1 and Th17 cell proliferation.

    Science.gov (United States)

    Lambracht-Washington, Doris; Qu, Bao-Xi; Fu, Min; Anderson, Larry D; Stüve, Olaf; Eagar, Todd N; Rosenberg, Roger N

    2011-08-01

    The pathogenesis of Alzheimer's disease (AD) has been strongly associated with the accumulation of amyloid beta (Aβ) peptides in brain, and immunotherapy targeting Aβ provides potential for AD prevention. A clinical trial in which AD patients were immunized with Aβ42 peptide was stopped when 6% of participants showed meningoencephalitis, apparently due to an inflammatory Th1 immune response. Previously, we and other have shown that Aβ42 DNA vaccination via gene gun generates a Th2 cellular immune response, which was shown by analyses of the respective antibody isotype profiles. We also determined that in vitro T cell proliferation in response to Aβ42 peptide re-stimulation was absent in DNA Aβ42 trimer-immunized mice when compared to Aβ42 peptide-immunized mice. To further characterize this observation prospectively and longitudinally, we analyzed the immune response in wild-type mice after vaccination with Aβ42 trimer DNA and Aβ42 peptide with Quil A adjuvant. Wild-type mice were immunized with short-term (1-3× vaccinations) or long-term (6× vacinations) immunization strategies. Antibody titers and isotype profiles of the Aβ42 specific antibodies, as well as cytokine profiles and cell proliferation studies from this longitudinal study were determined. Sufficient antibody titers to effectively reduce Aβ42, but an absent T cell proliferative response and no IFNγ or IL-17 secretion after Aβ42 DNA trimer immunization minimizes the risk of inflammatory activities of the immune system towards the self antigen Aβ42 in brain. Therefore, Aβ42 DNA trimer immunization has a high probability to be effective and safe to treat patients with early AD.

  17. Muscles provide protection during microbial infection by activating innate immune response pathways in Drosophila and zebrafish

    Directory of Open Access Journals (Sweden)

    Arunita Chatterjee

    2016-06-01

    Full Text Available Muscle contraction brings about movement and locomotion in animals. However, muscles have also been implicated in several atypical physiological processes including immune response. The role of muscles in immunity and the mechanism involved has not yet been deciphered. In this paper, using Drosophila indirect flight muscles (IFMs as a model, we show that muscles are immune-responsive tissues. Flies with defective IFMs are incapable of mounting a potent humoral immune response. Upon immune challenge, the IFMs produce anti-microbial peptides (AMPs through the activation of canonical signaling pathways, and these IFM-synthesized AMPs are essential for survival upon infection. The trunk muscles of zebrafish, a vertebrate model system, also possess the capacity to mount an immune response against bacterial infections, thus establishing that immune responsiveness of muscles is evolutionarily conserved. Our results suggest that physiologically fit muscles might boost the innate immune response of an individual.

  18. Mental health service responses to human trafficking: a qualitative study of professionals' experiences of providing care.

    Science.gov (United States)

    Domoney, Jill; Howard, Louise M; Abas, Melanie; Broadbent, Matthew; Oram, Sian

    2015-11-17

    Human trafficking is a global crime and human rights violation. Although research has demonstrated a high prevalence of mental disorder among trafficked people and that trafficked people are in contact with mental health services, little is known about mental health professionals' experiences of identifying and providing care for trafficked people. This study aimed to understand how people are identified as trafficked within mental health services and the challenges professionals experience in responding to trafficked people's mental health needs. Qualitative study of electronic health records of trafficked people in contact with secondary mental health services in South East London, England. Comprehensive clinical electronic health records for over 200,000 patients in contact with secondary mental health services in South London were searched and retrieved to identify trafficked patients. Content analysis was used to establish how people were identified as trafficked, and thematic analysis was used to explore the challenges experienced in responding to mental health needs. The sample included 130 trafficked patients, 95 adults and 35 children. In 43 % (41/95) of adult cases and 63 % (22/35) child cases, mental health professionals were informed that their patient was a potential victim of trafficking by another service involved in their patient's care. Cases were also identified through patients disclosing their experiences of exploitation and abuse. Key challenges faced by staff included social and legal instability, difficulties ascertaining history, patients' lack of engagement, availability of services, and inter-agency working. Training to increase awareness, encourage helpful responses, and inform staff about the available support options would help to ensure the mental health needs of trafficked people are met. Further research is needed to establish if these challenges are similar in other health settings.

  19. The Th1:Th2 Dichotomy of Pregnancy and Preterm Labour

    Directory of Open Access Journals (Sweden)

    Lynne Sykes

    2012-01-01

    Full Text Available Pregnancy is a unique immunological state in which a balance of immune tolerance and suppression is needed to protect the fetus without compromising the mother. It has long been established that a bias from the T helper 1 cytokine profile towards the T helper 2 profile contributes towards successful pregnancy maintenance. The majority of publications that report on aberrant Th1:Th2 balance focus on early pregnancy loss and preeclampsia. Over the last few decades, there has been an increased awareness of the role of infection and inflammation in preterm labour, and the search for new biomarkers to predict preterm labour continues. In this paper, we explore the evidence for an aberrant Th1:Th2 profile associated with preterm labour. We also consider the potential for its use in screening women at high risk of preterm labour and for prophylactic therapeutic measures for the prevention of preterm labour and associated neonatal adverse outcomes.

  20. Comparative Proteomics Provides Insights into Metabolic Responses in Rat Liver to Isolated Soy and Meat Proteins

    NARCIS (Netherlands)

    Song, Shangxin; Hooiveld, G.J.E.J.; Zhang, W.; Li, Mengjie; Zhoa, Fan; Xu, Xinglian; Müller, M.R.; Li, Chunbao; Zhou, Guanghong

    2016-01-01

    It has been reported that isolated dietary soy and meat proteins have distinct effects on physiology and liver gene expression, but the impact on protein expression responses are unknown. Because these may differ from gene expression responses, we investigated dietary protein-induced changes in

  1. Differential expression of CD300a/c on human TH1 and TH17 cells

    Directory of Open Access Journals (Sweden)

    Borrego Francisco

    2011-11-01

    Full Text Available Abstract Background Human memory CD4+ T cells can be either CD300a/c+ or CD300a/c- and subsequent analyses showed that CD4+ effector memory T (TEM cells are mostly CD300a/c+, whereas CD4+ central memory T (TCM cells have similar frequencies of CD300a/c+ and CD300a/c- cells. Results Extensive phenotypical and functional characterization showed that in both TCM and TEM cells, the CD300a/c+ subset contained a higher number of TH1 (IFN-γ producing cells. Alternatively, TH17 (IL-17a producing cells tend to be CD300a/c-, especially in the TEM subset. Further characterization of the IL-17a+ cells showed that cells that produce only this cytokine are mostly CD300a/c-, while cells that produce IL-17a in combination with other cytokines, especially IFN-γ, are mostly CD300a/c+, indicating that the expression of this receptor is associated with cells that produce IFN-γ. Co-ligation of the TCR and CD300a/c in CD4+ T cells inhibited Ca2+ mobilization evoked by TCR ligation alone and modulated IFN-γ production on TH1 polarized cells. Conclusion We conclude that the CD300a/c receptors are differentially expressed on human TH1 and TH17 cells and that their ligation is capable of modulating TCR mediated signals.

  2. Thermophysical and anion diffusion properties of (Ux,Th1−x)O2

    Science.gov (United States)

    Cooper, Michael W. D.; Murphy, Samuel T.; Fossati, Paul C. M.; Rushton, Michael J. D.; Grimes, Robin W.

    2014-01-01

    Using molecular dynamics, the thermophysical properties of the (Ux,Th1−x)O2 system have been investigated between 300 and 3600 K. The thermal dependence of lattice parameter, linear thermal expansion coefficient, enthalpy and specific heat at constant pressure is explained in terms of defect formation and diffusivity on the oxygen sublattice. Vegard's law is approximately observed for solid solution thermal expansion below 2000 K. Different deviations from Vegard's law above this temperature occur owing to the different temperatures at which the solid solutions undergo the superionic transition (2500–3300 K). Similarly, a spike in the specific heat, associated with the superionic transition, occurs at lower temperatures in solid solutions that have a high U content. Correspondingly, oxygen diffusivity is higher in pure UO2 than in pure ThO2. Furthermore, at temperatures below the superionic transition, oxygen mobility is notably higher in solid solutions than in the end members. Enhanced diffusivity is promoted by lower oxygen-defect enthalpies in (Ux,Th1−x)O2 solid solutions. Unlike in UO2 and ThO2, there is considerable variety of oxygen vacancy and oxygen interstitial sites in solid solutions generating a wide range of property values. Trends in the defect enthalpies are discussed in terms of composition and the lattice parameter of (Ux,Th1−x)O2. PMID:25383028

  3. Diisononyl phthalate induces asthma via modulation of Th1/Th2 equilibrium.

    Science.gov (United States)

    Hwang, Yun-Ho; Paik, Man-Jeong; Yee, Sung-Tae

    2017-04-15

    Diisononyl phthalate (DINP), a member of the phthalate family, is used to plasticize polyvinyl chloride (PVC). This chemical is known to enhance airway inflammation in the OVA-induced asthma model (adjuvant effects) and aggravate allergic dermatitis. Moreover, DINP enhances the production of interleukin-4 in activated CD4(+) T cells. However, the effect of DINP itself on the differentiation of naïve CD4(+) T cells into T helper cells (Th1/Th2) in vitro and allergic asthma in vivo has not yet been studied. In this study, DINP was shown to suppress the polarization of Th1 and enhance the polarization of Th2 from naïve CD4(+) T cells in vitro. Also, DINP induced allergic asthma via the production of IL-4, IL-5, IgE and IgG1 and the reduction of IFN-γ and IgG2a. Finally, we confirmed that exposure to DINP induces the infiltration of inflammatory cells and PAS positive cells and increases the expression of caspase-1 and caspase-3 in asthmatic mice. In conclusion, we suggest that DINP as an environmental pollutant or endocrine disruptor (ECD) induces asthma via the modulation of the Th1/Th2 equilibrium and production of Th2 mediated cytokines and immunoglobulin. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Role of Th1/Th2 cytokines in the diagnosis and prognostic evaluation of ankylosing spondylitis.

    Science.gov (United States)

    Wen, J T; Zhang, D H; Fang, P F; Li, M H; Wang, R J; Li, S H

    2017-03-16

    Ankylosing spondylitis (AS), a progressive disease of the spine, manifests as peripheral arthritis with tendon and ligament inflammation that restricts activity. AS is a rheumatoid autoimmune disease although the rheumatoid factor is absent in patients with AS. It is characterized by inflammatory changes such as elevated levels of serum inflammatory factors. The roles of Th1 and Th2 cytokines in autoimmune diseases are well known. However, the roles of these cytokines in the diagnosis and prognosis of AS is poorly understood. The aim of this study was to investigate the roles of Th1/Th2 cytokines in the diagnosis and prognosis of AS. The BASDAI activity, BASFI functional index, BASMI measurement score, and the levels of CRP and ESR were measured during the treatment of patients with active AS. The levels of IFN-γ and TNF-α (Th1 cytokines) and IL-4 and IL-10 (Th2 cytokines) were quantified. The levels of IL-4 and IL-10 were significantly low in the serum of patients with active AS, who also had high IFN-γ and TNF-α levels compared to those in the control individuals (P cytokines in patients with AS may reflect disease activity and prognosis.

  5. Turmeric (Curcuma longa) attenuates food allergy symptoms by regulating type 1/type 2 helper T cells (Th1/Th2) balance in a mouse model of food allergy.

    Science.gov (United States)

    Shin, Hee Soon; See, Hye-Jeong; Jung, Sun Young; Choi, Dae Woon; Kwon, Da-Ae; Bae, Min-Jung; Sung, Ki-Seung; Shon, Dong-Hwa

    2015-12-04

    Turmeric (Curcuma longa) has traditionally been used to treat pain, fever, allergic and inflammatory diseases such as bronchitis, arthritis, and dermatitis. In particular, turmeric and its active component, curcumin, were effective in ameliorating immune disorders including allergies. However, the effects of turmeric and curcumin have not yet been tested on food allergies. Mice were immunized with intraperitoneal ovalbumin (OVA) and alum. The mice were orally challenged with 50mg OVA, and treated with turmeric extract (100mg/kg), curcumin (3mg/kg or 30 mg/kg) for 16 days. Food allergy symptoms including decreased rectal temperature, diarrhea, and anaphylaxis were evaluated. In addition, cytokines, immunoglobulins, and mouse mast cell protease-1 (mMCP-1) were evaluated using ELISA. Turmeric significantly attenuated food allergy symptoms (decreased rectal temperature and anaphylactic response) induced by OVA, but curcumin showed weak improvement. Turmeric also inhibited IgE, IgG1, and mMCP-1 levels increased by OVA. Turmeric reduced type 2 helper cell (Th2)-related cytokines and enhanced a Th1-related cytokine. Turmeric ameliorated OVA-induced food allergy by maintaining Th1/Th2 balance. Furthermore, turmeric was confirmed anti-allergic effect through promoting Th1 responses on Th2-dominant immune responses in immunized mice. Turmeric significantly ameliorated food allergic symptoms in a mouse model of food allergy. The turmeric as an anti-allergic agent showed immune regulatory effects through maintaining Th1/Th2 immune balance, whereas curcumin appeared immune suppressive effects. Therefore, we suggest that administration of turmeric including various components may be useful to ameliorate Th2-mediated allergic disorders such as food allergy, atopic dermatitis, and asthma. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  6. Treatment with Bifidobacterium bifidum 17 partially protects mice from Th1-driven inflammation in a chemically induced model of colitis.

    Science.gov (United States)

    Philippe, David; Heupel, Esther; Blum-Sperisen, Stephanie; Riedel, Christian U

    2011-09-01

    Probiotics have been suggested as an alternative therapeutical approach in the intervention of inflammatory disorders of the gastrointestinal tract (GIT). Application of single strains or probiotic mixtures has shown promising results in animal models and patients of inflammatory bowel disease (IBD). We recently demonstrated potent inhibitory capacity of a Bifidobacterium bifidum S17 on LPS-induced inflammatory events in cell culture models using intestinal epithelial cells and verified these anti-inflammatory effects in two mouse models of colitis. In the present study we analyze the anti-inflammatory effect of this potential probiotic strain in a chemically-induced model of colitis in C57BL/6 mice. This model is characterized by a strong type 1T helper (Th1) response resembling Crohn's disease, one of the two most prevalent forms of IBD. We performed macroscopic analysis and determined the effect of B. bifidum S17 on the cytokine balance in biopsies of the colonic mucosa. While treatment with B. bifidum S17 only had a marginal effect on weight loss, no difference was observed in the macroscopic parameters. However, a significant reduction in histology scores and the levels of pro-inflammatory cytokines interleukin 1β (IL-1β), interleukin 6 (IL-6), keratinocyte-derived chemokine (KC) and the inflammatory markers cyclooxigenase 2 (Cox-2) and myeloperoxidase (MPO) was observed. These results indicate that treatment with B. bifidum S17 is able to partially inhibit the strong Th1-driven intestinal inflammation induced in our model of colitis. Copyright © 2010 Elsevier B.V. All rights reserved.

  7. Service Learning: Providing the Building Blocks for a Socially Responsible Nursing Role

    Science.gov (United States)

    Johnson, Judith M.

    2013-01-01

    An explanatory correlational study was conducted to explore whether and to what extent a relationship between hours of participation in service learning and commitment to social responsibility exists for students enrolled in pre-licensure baccalaureate-nursing programs currently participating in the Nursing Licensure Compact. The convenience…

  8. Response to Intervention: Providing Reading Intervention to Low Income and Minority Students

    Science.gov (United States)

    Graves, Emily; McConnell, Tess

    2014-01-01

    With a renewed focus on early intervention, teachers must address the difficulties students are having as early as possible to promote their progress. Culturally and linguistically diverse students may not respond to universal interventions that have shown efficiency for mainstream populations. In order for Response to Intervention to be…

  9. Providing Services for Students with Gifts and Talents within a Response-to-Intervention Framework

    Science.gov (United States)

    Johnsen, Susan K.; Parker, Sonia L.; Farah, Yara N.

    2015-01-01

    Response to intervention (RTI) was included in the 2004 reauthorization of the Individuals With Disabilities Education Act (IDEA), specifically as part of an assessment process to determine if a child has a disability. Although IDEA's focus is on students with disabilities, 10 states have developed policies that attend to students with gifts and…

  10. Targeting beta- and alpha-adrenergic receptors differentially shifts Th1, Th2, and inflammatory cytokine profiles in immune organs to attenuate adjuvant arthritis

    Directory of Open Access Journals (Sweden)

    Dianne eLorton

    2014-08-01

    Full Text Available The sympathetic nervous system (SNS regulates host defense responses and restores homeostasis. SNS-immune regulation is altered in rheumatoid arthritis (RA and rodent models of RA, characterized by nerve remodeling in immune organs and defective adrenergic receptor (AR signaling to immune cell targets that typically promotes or suppresses inflammation via α- and β2-AR activation, respectively, and indirectly drives humoral immunity by blocking Th1 cytokine secretion. Here, we investigate how β2-AR stimulation and/or α-AR blockade at disease onset affects disease pathology and cytokine profiles in relevant immune organs from male Lewis rats with adjuvant-induced arthritis (AA. Rats challenged to induce AA were treated with terbutaline (TERB, a β2-AR agonist (600 μg/kg/day and/or phentolamine (PHEN, an α-AR antagonist (5.0 mg/kg/day or vehicle from disease onset through severe disease. We report that in spleen, mesenteric (MLN and draining lymph node (DLN cells, TERB reduces proliferation, an effect independent of IL-2. TERB also fails to shift Th cytokines from a Th1 to Th2 profile in spleen and MLN (no effect on IFN-γ and DLN (greater IFN-γ cells. In splenocytes, TERB, PHEN and co-treatment (PT promotes an anti-inflammatory profile (greater IL-10 and lowers TNF-α (PT only. In DLN cells, drug treatments do not affect inflammatory profiles, except PT, which raised IL-10. In MLN cells, TERB or PHEN lowers MLN cell secretion of TNF-α or IL-10, respectively. Collectively, our findings indicate disrupted β2-AR, but not α-AR signaling in AA. Aberrant β2-AR signaling consequently derails the sympathetic regulation of lymphocyte expansion, Th cell differentiation, and inflammation in the spleen, DLNs and MLNs that is required for immune system homeostasis. Importantly, this study provides potential mechanisms through which reestablished balance between α- and β2-AR function in the immune system ameliorates inflammation and joint

  11. Early postoperative tumor marker responses provide a robust prognostic indicator for N3 stage gastric cancer.

    Science.gov (United States)

    Zhang, Qingrui; Qu, Hui; Sun, Guorui; Li, Zhiqiang; Ma, Shuzhen; Shi, Zhenxing; Zhao, Ensheng; Zhang, Hao; He, Qingsi

    2017-08-01

    The clinical significance of tumor markers after radical gastrectomy has not been well characterized. The purpose of this study is to evaluate the prognostic value of early postoperative tumor marker normalization in N3 stage gastric cancer (GC) patients. A total of 259 N3 stage GC patients with preoperatively elevated carcinoembryonic antigen (CEA, >5 ng/mL) or carbohydrate antigen 19-9 (CA19-9, >37 U/mL) levels underwent radical gastrectomy were analyzed retrospectively. Early postoperative tumor marker response was considered as a normalization of CEA or CA19-9 levels 4 weeks after surgery. The disease-free survival (DFS) and overall survival (OS) were analyzed. N3 stage GC patients were divided into N3a (n = 157) and N3b (n = 102) groups according to the 8th TNM stage system. Early tumor marker response was identified in 96 of 157 N3a patients (61.15%) and 57 of 102 N3b patients (55.88%). In N3 stage GC patients with a tumor marker response, significant increase was observed in both DFS (25.2 months vs 12.5 months, P early tumor marker response was an independent factor for DFS and OS in N3 stage GC, as well as for depth of invasion and metastatic lymph node rate (P Early postoperative CEA or CA19-9 normalization serves as a strong prognostic indicator in N3 stage GC. Both N3a and N3b patients with increased early postoperative tumor marker levels showed poor outcomes.

  12. Comparative proteomic analysis provides insight into cadmium stress responses in brown algae Sargassum fusiforme

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Aiqin; Xu, Tao [Alkali Soil Natural Environmental Science Center, Northeast Forestry University, Key Laboratory of Saline–alkali Vegetation Ecology Restoration in Oil Field, Ministry of Education, Harbin 150040 (China); Zou, Huixi [Zhejiang Provincial Key Laboratory for Subtropical Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035 (China); Pang, Qiuying, E-mail: qiuying@nefu.edu.cn [Alkali Soil Natural Environmental Science Center, Northeast Forestry University, Key Laboratory of Saline–alkali Vegetation Ecology Restoration in Oil Field, Ministry of Education, Harbin 150040 (China)

    2015-06-15

    Highlights: • Proteomic analysis of brown algae response different level Cd stress was performed. • Proteins involved in carbohydrate metabolism were reduced under 1 day Cd stress. • 5 days Cd stress induced glycolysis and citrate cycle related proteins. • Graphic depiction of different metabolic pathways response to Cd stress was framed. - Abstract: Sargassum fusiforme is one of the most widely consumed seaweeds in China, Korea and Japan. In this work, we performed growth analysis and comparative proteomics to investigate the molecular mechanisms of the response to 1 day and 5 days Cd stress in S. fusiforme. Our results showed a significant decrease in growth rate and an increase in Cd ion content in S. fusiforme in response to Cd treatment. Comparative proteomic analysis revealed 25 and 51 differentially expressed protein spots in S. fusiforme under 1 day and 5 days Cd stress, respectively. A great number of these proteins was metabolic enzymes involved in carbohydrate metabolism and energy metabolism. Many proteins involved in the processing of genetic information showed a decrease in abundance under 1 day Cd stress. In contrast, 9 of the identified protein spots primarily involved in genetic information processing and carbohydrate metabolism were greatly enriched under 5 days Cd stress. Overall, our investigation indicated that Cd stress negatively affects the metabolic activity of S. fusiforme through the down-regulation of key metabolic enzymes. In addition, S. fusiforme may adapt to 5 days Cd stress by promoting consumption of photoassimilates through the up-regulation of glycolysis and the citrate cycle to supply energy for survival.

  13. Comparative Proteomics Provides Insights into Metabolic Responses in Rat Liver to Isolated Soy and Meat Proteins.

    Science.gov (United States)

    Song, Shangxin; Hooiveld, Guido J; Zhang, Wei; Li, Mengjie; Zhao, Fan; Zhu, Jing; Xu, Xinglian; Muller, Michael; Li, Chunbao; Zhou, Guanghong

    2016-04-01

    It has been reported that isolated dietary soy and meat proteins have distinct effects on physiology and liver gene expression, but the impact on protein expression responses are unknown. Because these may differ from gene expression responses, we investigated dietary protein-induced changes in liver proteome. Rats were fed for 1 week semisynthetic diets that differed only regarding protein source; casein (reference) was fully replaced by isolated soy, chicken, fish, or pork protein. Changes in liver proteome were measured by iTRAQ labeling and LC-ESI-MS/MS. A robust set totaling 1437 unique proteins was identified and subjected to differential protein analysis and biological interpretation. Compared with casein, all other protein sources reduced the abundance of proteins involved in fatty acid metabolism and Pparα signaling pathway. All dietary proteins, except chicken, increased oxidoreductive transformation reactions but reduced energy and essential amino acid metabolic pathways. Only soy protein increased the metabolism of sulfur-containing and nonessential amino acids. Soy and fish proteins increased translation and mRNA processing, whereas only chicken protein increased TCA cycle but reduced immune responses. These findings were partially in line with previously reported transcriptome results. This study further shows the distinct effects of soy and meat proteins on liver metabolism in rats.

  14. Health provider responsiveness to social accountability initiatives in low- and middle-income countries: a realist review.

    Science.gov (United States)

    Lodenstein, Elsbet; Dieleman, Marjolein; Gerretsen, Barend; Broerse, Jacqueline E W

    2017-02-01

    Social accountability in the health sector has been promoted as a strategy to improve the quality and performance of health providers in low- and middle-income countries. Whether improvements occur, however, depends on the willingness and ability of health providers to respond to societal pressure for better care. This article uses a realist approach to review cases of collective citizen action and advocacy with the aim to identify key mechanisms of provider responsiveness. Purposeful searches for cases were combined with a systematic search in four databases. To be included in the review, the initiatives needed to describe at least one outcome at the level of frontline service provision. Some 37 social accountability initiatives in 15 countries met these criteria. Using a realist approach, retroductive analysis and triangulation of methods and sources were performed to construct Context-Mechanism-Outcome configurations that explain potential pathways to provider responsiveness. The findings suggest that health provider receptivity to citizens' demands for better health care is mediated by health providers' perceptions of the legitimacy of citizen groups and by the extent to which citizen groups provide personal and professional support to health providers. Some citizen groups activated political or formal bureaucratic accountability channels but the effect on provider responsiveness of such strategies was more mixed. Favourable contexts for health provider responsiveness comprise socio-political contexts in which providers self-identify as activists, health system contexts in which health providers depend on citizens' expertise and capacities, and health system contexts where providers have the self-perceived ability to change the system in which they operate. Rather than providing recipes for successful social accountability initiatives, the synthesis proposes a programme theory that can support reflections on the theories of change underpinning social

  15. Analysis of serum th1/th2 cytokine levels in patients with acute mumps infection

    Directory of Open Access Journals (Sweden)

    Jeevan Malaiyan

    2016-01-01

    Full Text Available Background: The mumps virus is frequently the causative agent of parotitis. There has been no study on serum cytokine levels of acute mumps parotitis except for a few which document cytokine levels in cerebrospinal fluid of mumps meningitis. It is with this notion, our study aimed to find Th1/Th2 cytokine levels from patients with acute mumps parotitis. Materials and Methods: Concentrations of mumps-specific IgM, mumps, measles, rubella-specific IgG antibody, and Th1/Th2 cytokines, namely interferon-g (IFN-g, interleukin-2 (IL-2, IL-4, and IL-10 were measured simultaneously in serum from 74 patients (42 pediatric and 32 adult cases, 40 healthy subjects (20 pediatric and 20 adults and in the supernatant of peripheral blood mononuclear cells stimulated with mumps virus genotype C which served as the positive control. Statistical significance was analyzed between each group by means of Mann-Whitney U-test, Kruskal-Wallis test, and Spearman′s rank correlation coefficient test. Results: IgM positivity confirmed acute infection in all 74 patients and of these 67 were vaccinated cases; however, very few of them (10/67 were positive for mumps IgG. We found that IFN-g, IL-2, and IL-10 showed a statistically significant increase in both pediatric and adult patients with acute mumps infection when compared to healthy controls and values were comparable to the positive control. Conclusion: The Th1 cells play important roles during the acute phase of mumps parotitis.

  16. Th1, Th2, and Th17 Cytokine Involvement in Thyroid Associated Ophthalmopathy

    Directory of Open Access Journals (Sweden)

    Jie Shen

    2015-01-01

    Full Text Available To determine serum cytokine profiles in Graves’ disease (GD patients with or without active and inactive thyroid associated ophthalmopathy (TAO, we recruited 65 subjects: 10 GD only (without TAO, 25 GD + active TAO, 20 GD + TAO, and 10 healthy controls. Liquid chip assay was used to measure serum Th1/Th2/Th17 cytokines including IFN-γ (interferon-gamma, TNF-α (tumor necrosis factor-alpha, IL-1α (interleukin-1 alpha, IL-1Ra (IL-1 receptor antagonist, IL-2, IL-4, IL-6, and IL-17 and two chemokines: RANTES (regulated upon activation, normal T cell expressed and secreted and IP-10 (IFN-γ-induced protein 10. Serum levels of TSH (thyroid stimulating hormone receptor autoantibodies (TRAb were measured using an enzyme linked immunosorbent assay. Compared with healthy controls, TAO patients showed significantly elevated serum levels of IFN-γ, TNF-α, IL-1α, IL-4, IL-6, IL-17, and IP-10. Comparing active and inactive TAO, serum Th1 cytokines IFN-γ and TNF-α were elevated in active TAO, while serum Th2 cytokine IL-4 was elevated in inactive TAO. Serum Th17 cytokine IL-17 was elevated in GD but reduced in both active and inactive TAO. A positive correlation was found between TRAb and IFN-γ, TNF-α, IL-1α, IL-2, IL-4, and IL-6. Taken together, serum Th1/Th2/Th17 cytokines and chemokines reflect TAO disease activity and may be implicated in TAO pathogenesis.

  17. TH1 and TH17 cells promote crescent formation in experimental autoimmune glomerulonephritis.

    Science.gov (United States)

    Hünemörder, Stefanie; Treder, Julia; Ahrens, Stefanie; Schumacher, Valéa; Paust, Hans-Joachim; Menter, Thomas; Matthys, Patrick; Kamradt, Thomas; Meyer-Schwesinger, Catherine; Panzer, Ulf; Hopfer, Helmut; Mittrücker, Hans-Willi

    2015-09-01

    Autoimmunity against the Goodpasture antigen α3IV-NC1 results in crescentic glomerulonephritis (GN). Both antibodies and T cells directed against α3IV-NC1 have been implicated in disease development and progression. Using the model of experimental autoimmune glomerulonephritis (EAG) in DBA/1 mice, we aimed to characterize the frequency and function of α3IV-NC1-specific CD4(+) T cells in the kidneys. DBA/1 mice repeatedly immunized with human α3IV-NC1 developed necrotizing/crescentic GN. Kidneys with crescentic GN contained CD4(+) cells responding to α3IV-NC1 with the production of IFN-γ or IL-17A, demonstrating the accumulation of both α3IV-NC1-specific TH1 and TH17 cells. To test the functional relevance of TH1 and TH17 cells, EAG was induced in DBA/1 mice deficient in IFN-γR, IL-17A or IL-23p19. Mice of all knockout groups mounted α3IV-NC1 IgG, developed nephrotic range proteinuria, and IgG deposition to the glomerular basement membranes at levels similar to immunized wild-type mice. However, all knockout groups showed significantly fewer glomerular crescents and attenuated tubulointerstitial damage. Our results suggest that both α3IV-NC1-specific TH1 and TH17 cells accumulate in the kidneys and are crucial for the development of necrotizing/crescentic GN. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  18. The response of substance use disorder treatment providers to changes in macroeconomic conditions.

    Science.gov (United States)

    Cantor, Jonathan; Stoller, Kenneth B; Saloner, Brendan

    2017-10-01

    To study how substance use disorder (SUD) treatment providers respond to changes in economic conditions. 2000-2012 National Survey of Substance Abuse Treatment Services (N-SSATS) which contains detailed information on specialty SUD facilities in the United States. We use fixed-effects regression to study how changes in economic conditions, proxied by state unemployment rates, impact treatment setting, accepted payment forms, charity care, offered services, special programs, and use of pharmacotherapies by specialty SUD treatment providers. Secondary data analysis in the N-SSATS. Our findings suggest a one percentage point increase in the state unemployment rate is associated with a 2.5% reduction in outpatient clients by non-profit providers and a 1.8% increase in the acceptance of private insurance as a form of payment overall. We find no evidence that inpatient treatment, the provision of charity care, offered services, or special programs are impacted by changes in the state unemployment rate. However, a one percentage point increase in the state unemployment rate leads to a 2.5% increase in the probability that a provider uses pharmacotherapies to treat addiction. Deteriorating economic conditions may increase financial pressures on treatment providers, prompting them to seek new sources of revenue or to change their care delivery models. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. 20 CFR 1002.261 - Who is responsible for funding any plan obligation to provide the employee with pension benefits?

    Science.gov (United States)

    2010-04-01

    ... obligation to provide the employee with pension benefits? 1002.261 Section 1002.261 Employees' Benefits... and Benefits Pension Plan Benefits § 1002.261 Who is responsible for funding any plan obligation to provide the employee with pension benefits? With the exception of multiemployer plans, which have separate...

  20. Relative Contribution of Th1 and Th17 Cells in Adaptive Immunity to Bordetella pertussis: Towards the Rational Design of an Improved Acellular Pertussis Vaccine

    Science.gov (United States)

    Ross, Pádraig J.; Allen, Aideen C.; Walsh, Kevin; Misiak, Alicja; Lavelle, Ed C.; McLoughlin, Rachel M.; Mills, Kingston H. G.

    2013-01-01

    Whooping cough caused by Bordetella pertussis is a re-emerging infectious disease despite the introduction of safer acellular pertussis vaccines (Pa). One explanation for this is that Pa are less protective than the more reactogenic whole cell pertussis vaccines (Pw) that they replaced. Although Pa induce potent antibody responses, and protection has been found to be associated with high concentrations of circulating IgG against vaccine antigens, it has not been firmly established that host protection induced with this vaccine is mediated solely by humoral immunity. The aim of this study was to examine the relative contribution of Th1 and Th17 cells in host immunity to infection with B. pertussis and in immunity induced by immunization with Pw and Pa and to use this information to help rationally design a more effective Pa. Our findings demonstrate that Th1 and Th17 both function in protective immunity induced by infection with B. pertussis or immunization with Pw. In contrast, a current licensed Pa, administered with alum as the adjuvant, induced Th2 and Th17 cells, but weak Th1 responses. We found that IL-1 signalling played a central role in protective immunity induced with alum-adsorbed Pa and this was associated with the induction of Th17 cells. Pa generated strong antibody and Th2 responses, but was fully protective in IL-4-defective mice, suggesting that Th2 cells were dispensable. In contrast, Pa failed to confer protective immunity in IL-17A-defective mice. Bacterial clearance mediated by Pa-induced Th17 cells was associated with cell recruitment to the lungs after challenge. Finally, protective immunity induced by an experimental Pa could be enhanced by substituting alum with a TLR agonist that induces Th1 cells. Our findings demonstrate that alum promotes protective immunity through IL-1β-induced IL-17A production, but also reveal that optimum protection against B. pertussis requires induction of Th1, but not Th2 cells. PMID:23592988

  1. Provider responsibility and system redesign: two sides of the same coin.

    Science.gov (United States)

    Richardson, William C; Corrigan, Janet M

    2003-01-01

    Patient safety is a serious problem that health care professionals and hospitals must confront. The health care delivery system must be redesigned. Health care professionals have a moral and ethical responsibility to actively participate in the development and operation of well-designed care processes. Efforts to redesign the delivery system will be most effective if accompanied by changes in the environment that shapes care delivery. Health care leadership must also focus attention on identifying the types of environmental changes needed at different levels, and on the part of specific stakeholders, to allow model twenty-first-century community health systems to develop.

  2. Four criteria to evaluate providers' service-delivery response to new contraceptive introduction.

    Science.gov (United States)

    León, Federico R; Arévalo, Marcos; Lundgren, Rebecka; Jennings, Victoria; Huapaya, Ana; Panfichi, Rosario

    2007-08-01

    This article presents an evaluation framework developed to assess the first-level effects of introducing the Standard Days Method (SDM) in Peru Ministry of Health clinics. Four questions are asked: 1) To what extent do providers routinely achieve SDM service delivery standards? 2) Is the time invested in SDM delivery consistent with program norms? 3) How does SDM delivery compare with delivery of established methods? and 4) How does SDM introduction affect delivery of established methods? A study at 62 clinics demonstrated the framework's usefulness. The Standard Days Method introduction had positive overall effects on the quality of care but provider training needed adjustments.

  3. Oral Administration of p-Hydroxycinnamic Acid Attenuates Atopic Dermatitis by Downregulating Th1 and Th2 Cytokine Production and Keratinocyte Activation.

    Directory of Open Access Journals (Sweden)

    Hyun-Su Lee

    Full Text Available Atopic dermatitis (AD is a complex disease that is caused by various factors, including environmental change, genetic defects, and immune imbalance. We previously showed that p-hydroxycinnamic acid (HCA isolated from the roots of Curcuma longa inhibits T-cell activation without inducing cell death. Here, we demonstrated that oral administration of HCA in a mouse model of ear AD attenuates the following local and systemic AD manifestations: ear thickening, immune-cell infiltration, production of AD-promoting immunoregulatory cytokines in ear tissues, increased spleen and draining lymph node size and weight, increased pro-inflammatory cytokine production by draining lymph nodes, and elevated serum immunoglobulin production. HCA treatment of CD4+ T cells in vitro suppressed their proliferation and differentiation into Th1 or Th2 and their Th1 and Th2 cytokine production. HCA treatment of keratinocytes lowered their production of the pro-inflammatory cytokines that drive either Th1 or Th2 responses in AD. Thus, HCA may be of therapeutic potential for AD as it acts by suppressing keratinocyte activation and downregulating T-cell differentiation and cytokine production.

  4. Views on Logistics, Candid Voices, Providing Responsive Logistics Support: Applying LEAN Thinking to Logistics

    Science.gov (United States)

    1999-10-01

    repair, production, transportation, etc.) must provide customers with what they need when they need it. It must also minimize the cost to the customer . What...repair, produce or purchase things based on forecasted demands. However, in order to minimize the cost to the customer , the logistics system must repair

  5. Enhanced Th1/Th17 Functions of CD161+ CD8+ T Cells in Mucosal Tissues of Rhesus Macaques.

    Directory of Open Access Journals (Sweden)

    Namita Rout

    Full Text Available Expression of the C-type lectin-like receptor CD161 by human T cells is associated with type-17 responses, which play critical regulatory roles in immunity and inflammation at mucosal sites. However, the functions of CD161-expressing T cells in macaques, the pre-clinical model of several human diseases, remain unknown. This study examined the phenotypic and functional characteristics of CD161+ T cells in peripheral blood, mucosal tissues and lymph nodes of rhesus macaques. Majority of CD161-expressing T cells in peripheral blood and lung/intestinal mucosal tissues of rhesus macaques were found to be CD8+CD4- in phenotype. There was a significant enrichment of CD161+CD8+ T cells in the lungs and colonic mucosa (16.1%±6.6 and 16.8%±5.7 in comparison to peripheral blood (4.2%±1.2 and mesenteric lymph nodes (1.3%±0.8. Regardless of the tissue compartment, CD161+CD8+ T cells mainly comprised of γδ T cells and TCR Vα7.2+ MAIT cells (up to 80%, and displayed Th1 and Th17 cytokine responses to mitogen stimulation. Mucosal CD161+CD8+ T cells were characterized by very high expression of CD69, a recent activation marker that is preferentially expressed on tissue resident cells. Furthermore, lung and colonic mucosal CD161+CD8+ T cells showed enhanced IFN-γ, IL-17, and Perforin production in comparison to those in blood. Thus, macaque CD161+CD8+ T cells represent mucosal tissue-homing innate-like CD8+ T-cell populations with Th1/Th17 type cytokine and cytotoxic effector functions that can potentially enhance the recruitment of adaptive immune cells and control initial pathogen burden/dissemination in tissues. Analysis of their role in early immune responses to mucosal pathogens will be valuable in the design of vaccines and therapeutics.

  6. Molecular insight into the immune up-regulatory properties of the leaf extract of Ashwagandha and identification of Th1 immunostimulatory chemical entity.

    Science.gov (United States)

    Khan, Sheema; Malik, Fayaz; Suri, Krishan A; Singh, Jaswant

    2009-10-09

    Withania somnifera, commonly called Ashwagandha in the Indian traditional system of medicine has been reported for several pharmacological activities. This study demonstrates, for the first time, the potential role of the chemically standardized leaf extract of W. somnifera (WSL) and it's identified component in activating immune system. WSL enhanced Th1 cytokine IFN-gamma expression in Con A primed splenocytes in vitro. When given orally for 2 weeks to BALB/c mice immunized with emulsion of OVA in Freund's adjuvant (OVA-FCA), it caused dose-dependent proliferation of T cells and improved their ability to secrete IL-2 and IFN-gamma, but moderately down-regulated Th2 cytokine IL-4. Flow cytometric analysis of lymphocyte surface markers of T cells CD3(+), CD4(+) and CD8(+), and B cells CD19(+) indicated prominent enhancement in proliferation and differentiation of lymphocytes. Further, the effect of WSL in immunized mice elicited up-regulation of beta-integrins LFA (CD11a) and Mac-1 (CD11b) in splenocytes. Co-stimulatory molecules CD80 and CD86 that are important secondary signals for the activation of immune system elicited remarkable enhanced expression when observed in spleen-derived macrophages isolated from WSL treated mice. Chemical standardization of WSL suggested that the withanolide 2,3 dihydro-3-sulphonile withanone is a major constituent of WSL responsible for skewing to Th1 immune polarization by stimulating the expression of IFN-gamma and B cell switch over to secrete IgG2a while simultaneously enhancing the expression of co-stimulatory molecules and integrins. These studies demonstrate the possible usefulness of WSL and its major constituent WSL-2 as Th1 immune adjuvants for chronic infectious ailments where patients suffer from weakened Th1 immunity.

  7. The Leishmania promastigote surface antigen-2 (PSA-2) is specifically recognised by Th1 cells in humans with naturally acquired immunity to L. major

    DEFF Research Database (Denmark)

    Kemp, M; Handman, E; Kemp, K

    1998-01-01

    The promastigote surface antigen-2 (PSA-2) is a Leishmania parasite antigen, which can induce Th1-mediated protection against murine leishmaniasis when used as a vaccine. To evaluate PSA-2 as a human vaccine candidate the specific T-cell response to PSA-2 was characterised in individuals immune...... to cutaneous leishmaniasis. Peripheral blood mononuclear cells from Sudanese individuals with a past history of self-healing cutaneous leishmaniasis proliferated vigorously in response to PSA-2 isolated from Leishmania major, whereas the antigen did not activate cells from presumably unexposed Danes...... and that these cells were the major source of interferon-gamma. The results show that Th1-like cells recognising PSA-2 are expanded during infection by L. major and that they maintain their Th1-like cytokine profile upon reactivation in vitro. Since immunity to cutaneous leishmaniasis is mediated by antigen...

  8. Response diversity to land use occurs but does not consistently stabilise ecosystem services provided by native pollinators.

    Science.gov (United States)

    Cariveau, Daniel P; Williams, Neal M; Benjamin, Faye E; Winfree, Rachael

    2013-07-01

    More diverse biological communities may provide ecosystem services that are less variable over space or time. However, the mechanisms underlying this relationship are rarely investigated empirically in real-world ecosystems. Here, we investigate how a potentially important stabilising mechanism, response diversity, the differential response to environmental change among species, stabilises pollination services against land-use change. We measured crop pollination services provided by native bees across land-use gradients in three crop systems. We found that bee species responded differentially to increasing agricultural land cover in all three systems, demonstrating that response diversity occurs. Similarly, we found response diversity in pollination services in two of the systems. However, there was no evidence that response diversity, in general, stabilised ecosystem services. Our results suggest that either response diversity is not the primary stabilising mechanism in our system, or that new measures of response diversity are needed that better capture the stabilising effects it provides. © 2013 John Wiley & Sons Ltd/CNRS.

  9. An exploratory typology of provider responses that encourage and discourage conversation about complementary and integrative medicine during routine oncology visits.

    Science.gov (United States)

    Koenig, Christopher J; Ho, Evelyn Y; Trupin, Laura; Dohan, Daniel

    2015-07-01

    To characterize how providers respond to patient mentions of complementary and integrative medicine (CIM) during routine oncology visits. Ethnographic methods were used over a two and a half year period with 82 advanced cancer patients and their providers across four oncology clinics. Participant observation fieldnotes were analyzed using Discourse Analysis. CIM was mentioned in 78/229 (34%) of the total observed visits. Patients initiated talk about CIM (76%) more than providers (24%). Patients mentioning CIM may indicate a preference for or interest in non-pharmacological adjunctive treatment options. Providers' responses inhibited further talk in 44% of observations and promoted talk in 56% of observations. How providers respond may indicate their willingness to discuss a range of treatment options and to collaboratively engage in treatment decision-making. Provider responses that inhibited CIM conversation passed on the opportunity to discuss patient preferences, and responses that promoted further conversation helped counsel patients about appropriate CIM use. Promoting discussion did not require additional time or extensive knowledge about CIM. Providers can facilitate high quality communication without endorsing CIM to help patients make treatment decisions and to evaluate CIM appropriateness in response to patient values and preferences. Published by Elsevier Ireland Ltd.

  10. Comparative sodium transport patterns provide clues for understanding salinity and metal responses in aquatic insects.

    Science.gov (United States)

    Scheibener, S A; Richardi, V S; Buchwalter, D B

    2016-02-01

    The importance of insects in freshwater ecosystems has led to their extensive use in ecological monitoring programs. As freshwater systems are increasingly challenged by salinization and metal contamination, it is important to understand fundamental aspects of aquatic insect physiology (e.g., osmoregulatory processes) that contribute to insect responses to these stressors. Here we compared the uptake dynamics of Na as NaCl, NaHCO3 and Na2SO4 in the caddisfly Hydropsyche betteni across a range of Na concentrations (0.06-15.22 mM) encompassing the vast majority of North American freshwater ecosystems. Sulfate as the major anion resulted in decreased Na uptake rates relative to the chloride and bicarbonate salts. A comparison of Na (as NaHCO3) turnover rates in the caddisfly Hydropsyche sparna and the mayfly Maccaffertium sp. revealed different patterns in the 2 species. Both species appeared to tightly regulate their whole body sodium concentrations (at ∼47±1.8 μmol/g wet wt) across a range of Na concentrations (0.06-15.22 mM) over 7 days. However, at the highest Na concentration (15.22 mM), Na uptake rates in H. sparna (419.1 μM Na g(-1) hr(-1) wet wt) appeared close to saturation while Na uptake rates in Maccaffertium sp. were considerably faster (715 g μM Na g(-1) hr(-1) wet wt) and appeared to not be close to saturation. Na efflux studies in H. sparna revealed that loss rates are commensurate with uptake rates and are responsive to changes in water Na concentrations. A comparison of Na uptake rates (at 0.57 mM Na) across 9 species representing 4 major orders (Ephemeroptera, Plecoptera, Trichoptera and Diptera) demonstrated profound physiological differences across species after accounting for the influence of body weight. Faster Na uptake rates were associated with species described as being sensitive to salinization in field studies. The metals silver (Ag) and copper (Cu), known to be antagonistic to Na uptake in other aquatic taxa did not generally

  11. Th1 and Th2 cytokine profiles induced by hepatitis C virus F protein in peripheral blood mononuclear cells from chronic hepatitis C patients.

    Science.gov (United States)

    Yue, Ming; Deng, Xiaozhao; Zhai, Xiangjun; Xu, Ke; Kong, Jing; Zhang, Jinhai; Zhou, Zhenxian; Yu, Xiaojie; Xu, Xiaodong; Liu, Yunxi; Zhu, Danyan; Zhang, Yun

    2013-05-01

    Th1 and Th2 cytokine response has been confirmed to be correlated with the pathogenesis of HCV infection. The aim of the study is to investigate the Th1 and Th2 cytokine profiles induced by HCV alternate reading frame protein (F protein) in chronic hepatitis C patients. We assessed the immune responses specific to HCV F protein in 55 chronic HCV patients. IFN-γ, IL-2, IL-4 and IL-5 secretion by peripheral blood mononuclear cells (PBMC) post F protein stimulation were compared among HCV patients and healthy donors. Finally, the associations between HCV F protein and HLA class II alleles were explored. We found that the seroprevalence of anti-F antibodies in HCV-related hepatocellular carcinoma (HCC) patients was significantly higher than that of patients without HCC, but such a significant difference in humoral immune responses to F protein was not observed in HCV 1b-infected- and non-HCV 1b-infected-patients. Additionally, the PBMC proliferation of HCC patients was significantly lower than that of patients without HCC. Furthermore, F protein stimulation of PBMCs from F-seropositive patients resulted in Th2 biased cytokine responses (significantly decreased IFN-γ and/or IL-2 and significantly increased IL-4 and/or IL-5 levels) that reportedly may contribute to HCC progression and pathogenesis. However, no significant difference in the association between HCV F protein and HLA-DRB1*0201, 0301, 0405, 1001 and HLA-DQB1*0201, 0401, 0502, 0602 was observed in this study. These findings suggest that F protein may contribute to the HCV-associated bias in Th1/Th2 responses of chronic hepatitis C patients including the progress of HCC pathogenesis. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Dynamic ABCG2 expression in human embryonic stem cells provides the basis for stress response.

    Science.gov (United States)

    Erdei, Zsuzsa; Sarkadi, Balázs; Brózik, Anna; Szebényi, Kornélia; Várady, György; Makó, Veronika; Péntek, Adrienn; Orbán, Tamás I; Apáti, Ágota

    2013-03-01

    ABCG2 is a plasma membrane multidrug transporter with an established role in the cancer drug-resistance phenotype. This protein is expressed in a variety of tissues, including several types of stem cell. Although ABCG2 is not essential for life, knock-out mice were found to be hypersensitive to xenobiotics and had reduced levels of the side population of hematopoietic stem cells. Previously we have shown that ABCG2 is present in human embryonic stem cell (hESC) lines, with a heterogeneous expression pattern. In this study we examined this heterogeneity, and investigated whether it is related to stress responses in hESCs. We did not find any difference between expression of pluripotency markers in ABCG2-positive and negative hESCs; however, ABCG2-expressing cells had a higher growth rate after cell separation. We found that some harmful conditions (physical stress, drugs, and UV light exposure) are tolerated much better in the presence of ABCG2 protein. This property can be explained by the transporter function which eliminates potential toxic metabolites accumulated during stress conditions. In contrast, mild oxidative stress in hESCs caused rapid internalization of ABCG2, indicating that some environmental factors may induce removal of this transporter from the plasma membrane. On the basis of these results we suggest that a dynamic balance of ABCG2 expression at the population level has the advantage of enabling prompt response to changes in the cellular environment. Such actively maintained heterogeneity might be of evolutionary benefit in protecting special cell types, including pluripotent stem cells.

  13. Electro-acupuncture at Acupoint ST36 Ameliorates Inflammation and Regulates Th1/Th2 Balance in Delayed-Type Hypersensitivity.

    Science.gov (United States)

    Wang, Zhigang; Chen, Tao; Long, Man; Chen, Longyun; Wang, Lei; Yin, Nina; Chen, Zebin

    2017-04-01

    Increasing evidence indicates anti-allergic and anti-inflammatory effects of electro-acupuncture (EA) therapy. However, its underlying mechanism on delayed-type hypersensitivity (DTH), a classic allergic inflammatory disease, still remains unclear. In this study, we aimed to explore the immunomodulatory mechanism of EA intervention in a mouse model of ovalbumin (OVA)-induced DTH. Mice were randomly divided into four groups: Control, OVA-DTH, DTH + EA, DTH + Sham. "Zusanli" acupoint (ST36) was used for DTH + EA, whereas a non-acupoint (localized 5 mm below the "Zusanli" acupoint) was selected for DTH + Sham. Footpad thickness was checked, and the infiltration of inflammatory cells was estimated by hematoxylin and eosin staining. Levels of IgG and IgE in serum of different groups and inflammatory cytokines in the supernatants from homogenized footpads, including IFN-γ, TNF-α, IL-4, and IL-5, were determined by ELISA. Cell proliferation of spleen lymphocytes was assayed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT). The frequency of CD4 + IFN-γ + and CD4 + IL-4 + T cells was analyzed with flow cytometry. In addition, the mRNA and protein expression of T-bet and GATA-3 were evaluated by real-time PCR and Western blotting, respectively. Our data showed EA treatment at acupoint ST36 relieved the pathological progression of DTH responses via reduction in footpad swelling, infiltration of inflammatory cells, levels of IgG and IgE as well as decreased production of IFN-γ and TNF-α in homogenized footpad tissue. Moreover, detailed studies were performed revealing that EA attenuated the percentage of CD4 + IFN-γ + T cells and prevented Th cells differentiation into Th1 cells, and this results from inhibiting secretion of IFN-γ and suppressing expression of T-bet, an IFN-γ transcription factor. The results indicated that EA treatment improved Th1-mediated allergic skin inflammation via restoring Th1/Th2 balance by curbing Th1

  14. Perceptions of Water Ownership, Water Management, and the Responsibility of Providing Clean Water

    Directory of Open Access Journals (Sweden)

    Jacqueline Noga

    2013-11-01

    Full Text Available Perceptions of water and water related issues still render many under-researched topics. This study aims to further our knowledge regarding people’s perceptions of water and our understanding about the different ways individuals use water. The authors asked the question: Does the way an individual perceives water (i.e., as a commodity, a human right, private resource, public resource and/or natural resource influence consumption and conservation of water, and sentiments towards control and allocation of water? An exploratory online questionnaire was designed to generate qualitative and quantitative data of survey participants’ perceptions, beliefs and actions towards water issues, such as overconsumption and scarcity. Data analysis included comparison of the quantitative data regarding the non-statistical association between how an individual perceives water and the individual’s beliefs, as well as qualitative analysis of the comments using an iterative pattern coding technique. One hundred and sixty four individuals participated in the survey (75% completion rate and over 430 comments were made. Themes that emerged from the comments included: responsibility, scarcity, the value of water, knowledge gained and education needed. Comparison of the different perceptions of water revealed that different perceptions of what water is resulted in different beliefs about what the cost of water should be. These findings have implications for future water use, including what needs to change in order to increase appreciation for water issues.

  15. Professional ethics in extreme circumstances: responsibilities of attending physicians and healthcare providers in hunger strikes.

    Science.gov (United States)

    Irmak, Nurbay

    2015-08-01

    Hunger strikes potentially present a serious challenge for attending physicians. Though rare, in certain cases, a conflict can occur between the obligations of beneficence and autonomy. On the one hand, physicians have a duty to preserve life, which entails intervening in a hunger strike before the hunger striker loses his life. On the other hand, physicians' duty to respect autonomy implies that attending physicians have to respect hunger strikers' decisions to refuse nutrition. International medical guidelines state that physicians should follow the strikers' unpressured advance directives. When physicians encounter an unconscious striker, in the absence of reliable advance directives, the guidelines advise physicians to make a decision on the basis of the patient's values, previously expressed wishes, and best interests. I argue that if there are no advance directives and the striker has already lost his competence, the physician has the responsibility to resuscitate the striker. Once the striker regains his decision-making capacity, he should be asked about his decision. If he is determined to continue fasting and refuses treatment, the physician has a moral obligation to respect this decisions and follow his advance directives.

  16. Transcriptome comparison and gene coexpression network analysis provide a systems view of citrus response to 'Candidatus Liberibacter asiaticus' infection.

    Science.gov (United States)

    Zheng, Zhi-Liang; Zhao, Yihong

    2013-01-16

    Huanglongbing (HLB) is arguably the most destructive disease for the citrus industry. HLB is caused by infection of the bacterium, Candidatus Liberibacter spp. Several citrus GeneChip studies have revealed thousands of genes that are up- or down-regulated by infection with Ca. Liberibacter asiaticus. However, whether and how these host genes act to protect against HLB remains poorly understood. As a first step towards a mechanistic view of citrus in response to the HLB bacterial infection, we performed a comparative transcriptome analysis and found that a total of 21 Probesets are commonly up-regulated by the HLB bacterial infection. In addition, a number of genes are likely regulated specifically at early, late or very late stages of the infection. Furthermore, using Pearson correlation coefficient-based gene coexpression analysis, we constructed a citrus HLB response network consisting of 3,507 Probesets and 56,287 interactions. Genes involved in carbohydrate and nitrogen metabolic processes, transport, defense, signaling and hormone response were overrepresented in the HLB response network and the subnetworks for these processes were constructed. Analysis of the defense and hormone response subnetworks indicates that hormone response is interconnected with defense response. In addition, mapping the commonly up-regulated HLB responsive genes into the HLB response network resulted in a core subnetwork where transport plays a key role in the citrus response to the HLB bacterial infection. Moreover, analysis of a phloem protein subnetwork indicates a role for this protein and zinc transporters or zinc-binding proteins in the citrus HLB defense response. Through integrating transcriptome comparison and gene coexpression network analysis, we have provided for the first time a systems view of citrus in response to the Ca. Liberibacter spp. infection causing HLB.

  17. God’s immanency in Abraham’s response to revelation: from providence to omnipresence

    Directory of Open Access Journals (Sweden)

    Ciocan Tudor Cosmin

    2016-03-01

    Full Text Available My assertion is that God’s biblical image may not reflect entirely His existence in itself as well as His revealed image. Even if God in Himself is both transcendent and immanent at the same time, and He is revealing accordingly in the history of humankind, still the image of God constructed in the writings of the Old Testament is merely the perspective made upon God by His followers to whom the He has revealed. That could be the reason why for centuries God’s biblical image seems to emphasize more His immanence, starting with Pentateuch, where God cohabites with Adam on Earth, then He reveals Himself to Abraham and Moses and so on. Somewhere, after the Babylonian exile, the image suffers slightly differences tilting towards God’s transcendence. In a path already created and grounded by Israel’s ancestors, even this new color of transcendence bears the nuances of immanence. How can this be possible? Let’s take a look on the revelation received by Abraham from God and see how this can fit the profile. Instead of the transcendence of God regarded by others in the differentness of Yahweh appointed by Abraham in his walking out of Mesopotamia, I will prove otherwise, that Abraham is on the contrary proving God’s immanency in this very differentness of His in relation with other gods by providence and omnipresence, indwelling His creation.

  18. Comparative proteomic analyses provide new insights into low phosphorus stress responses in maize leaves.

    Directory of Open Access Journals (Sweden)

    Kewei Zhang

    Full Text Available Phosphorus deficiency limits plant growth and development. To better understand the mechanisms behind how maize responds to phosphate stress, we compared the proteome analysis results of two groups of maize leaves that were treated separately with 1,000 µM (control, +P and 5 µM of KH2PO4 (intervention group, -P for 25 days. In total, 1,342 protein spots were detected on 2-DE maps and 15.43% had changed (P<0.05; ≥1.5-fold significantly in quantity between the +P and -P groups. These proteins are involved in several major metabolic pathways, including photosynthesis, carbohydrate metabolism, energy metabolism, secondary metabolism, signal transduction, protein synthesis, cell rescue and cell defense and virulence. The results showed that the reduction in photosynthesis under low phosphorus treatment was due to the down-regulation of the proteins involved in CO2 enrichment, the Calvin cycle and the electron transport system. Electron transport and photosynthesis restrictions resulted in a large accumulation of peroxides. Maize has developed many different reactive oxygen species (ROS scavenging mechanisms to cope with low phosphorus stress, including up-regulating its antioxidant content and antioxidase activity. After being subjected to phosphorus stress over a long period, maize may increase its internal phosphorus utilization efficiency by altering photorespiration, starch synthesis and lipid composition. These results provide important information about how maize responds to low phosphorus stress.

  19. Emergency medical services response to active shooter incidents: provider comfort level and attitudes before and after participation in a focused response training program.

    Science.gov (United States)

    Jones, Jerrilyn; Kue, Ricky; Mitchell, Patricia; Eblan, Gary; Dyer, K Sophia

    2014-08-01

    Emergency Medical Services (EMS) routinely stage in a secure area in response to active shooter incidents until the scene is declared safe by law enforcement. Due to the time-sensitive nature of injuries at these incidents, some EMS systems have adopted response tactics utilizing law enforcement protection to expedite life-saving medical care. Describe EMS provider perceptions of preparedness, adequacy of training, and general attitudes toward active shooter incident response after completing a tactical awareness training program. An unmatched, anonymous, closed-format survey utilizing a five-point Likert scale was distributed to participating EMS providers before and after a focused training session on joint EMS/police active shooter rescue team response. Descriptive statistics were used to compare survey results. Secondary analysis of responses based on prior military or tactical medicine training was performed using a chi-squared analysis. Two hundred fifty-six providers participated with 88% (225/256) pretraining and 88% (224/256) post-training surveys completed. Post-training, provider agreement that they felt adequately prepared to respond to an active shooter incident changed from 41% (92/225) to 89% (199/224), while agreement they felt adequately trained to provide medical care during an active shooter incident changed from 36% (82/225) to 87% (194/224). Post-training provider agreement that they should never enter a building with an active shooter changed from 73% (165/225) to 61% (137/224). Among the pretraining surveys, significantly more providers without prior military or tactical experience agreed they should never enter a building with an active shooter until the scene was declared safe (78% vs 50%, P = .002), while significantly more providers with prior experience felt both adequately trained to provide medical care in an active shooter environment (56% vs 31%, P = .007) and comfortable working jointly with law enforcement within a building if a

  20. Combining network modeling and gene expression microarray analysis to explore the dynamics of Th1 and Th2 cell regulation.

    Science.gov (United States)

    Pedicini, Marco; Barrenäs, Fredrik; Clancy, Trevor; Castiglione, Filippo; Hovig, Eivind; Kanduri, Kartiek; Santoni, Daniele; Benson, Mikael

    2010-12-16

    Two T helper (Th) cell subsets, namely Th1 and Th2 cells, play an important role in inflammatory diseases. The two subsets are thought to counter-regulate each other, and alterations in their balance result in different diseases. This paradigm has been challenged by recent clinical and experimental data. Because of the large number of genes involved in regulating Th1 and Th2 cells, assessment of this paradigm by modeling or experiments is difficult. Novel algorithms based on formal methods now permit the analysis of large gene regulatory networks. By combining these algorithms with in silico knockouts and gene expression microarray data from human T cells, we examined if the results were compatible with a counter-regulatory role of Th1 and Th2 cells. We constructed a directed network model of genes regulating Th1 and Th2 cells through text mining and manual curation. We identified four attractors in the network, three of which included genes that corresponded to Th0, Th1 and Th2 cells. The fourth attractor contained a mixture of Th1 and Th2 genes. We found that neither in silico knockouts of the Th1 and Th2 attractor genes nor gene expression microarray data from patients with immunological disorders and healthy subjects supported a counter-regulatory role of Th1 and Th2 cells. By combining network modeling with transcriptomic data analysis and in silico knockouts, we have devised a practical way to help unravel complex regulatory network topology and to increase our understanding of how network actions may differ in health and disease.

  1. Interleukin-6 Induced "Acute" Phenotypic Microenvironment Promotes Th1 Anti-Tumor Immunity in Cryo-Thermal Therapy Revealed By Shotgun and Parallel Reaction Monitoring Proteomics.

    Science.gov (United States)

    Xue, Ting; Liu, Ping; Zhou, Yong; Liu, Kun; Yang, Li; Moritz, Robert L; Yan, Wei; Xu, Lisa X

    2016-01-01

    Cryo-thermal therapy has been emerged as a promising novel therapeutic strategy for advanced breast cancer, triggering higher incidence of tumor regression and enhanced remission of metastasis than routine treatments. To better understand its anti-tumor mechanism, we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare N-glycoproteome changes in 94 serum samples with and without treatment. We quantified 231 highly confident N-glycosylated proteins using iTRAQ shotgun proteomics. Among them, 53 showed significantly discriminated regulatory patterns over the time course, in which the acute phase response emerged as the most enhanced pathway. The anti-tumor feature of the acute response was further investigated using parallel reaction monitoring target proteomics and flow cytometry on 23 of the 53 significant proteins. We found that cryo-thermal therapy reset the tumor chronic inflammation to an "acute" phenotype, with up-regulation of acute phase proteins including IL-6 as a key regulator. The IL-6 mediated "acute" phenotype transformed IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN-γ and IL-12 production, augmented complement system activation and CD86(+)MHCII(+) dendritic cells maturation and enhanced the proliferation of Th1 memory cells. In addition, we found an increased production of tumor progression and metastatic inhibitory proteins under such "acute" environment, favoring the anti-metastatic effect. Moreover, cryo-thermal on tumors induced the strongest "acute" response compared to cryo/hyperthermia alone or cryo-thermal on healthy tissues, accompanying by the most pronounced anti-tumor immunological effect. In summary, we demonstrated that cryo-thermal therapy induced, IL-6 mediated "acute" microenvironment shifted the tumor chronic microenvironment from Th2 immunosuppressive and pro-tumorigenic to Th1 immunostimulatory and tumoricidal state. Moreover, the magnitude of "acute" and "danger" signals play a key

  2. Big Brother’s Little Helpers: The Right to Privacy and the Responsibility of Internet Service Providers

    Directory of Open Access Journals (Sweden)

    Yael Ronen

    2015-02-01

    Full Text Available Following the 2013 revelations on the extent of intelligence gathering through internet service providers, this article concerns the responsibility of internet service providers (ISPs involved in disclosure of personal data to government authorities under the right to privacy, by reference to the developing, non-binding standards applied to businesses under the Protect, Respect and Remedy Framework. The article examines the manner in which the Framework applies to ISPs and looks at measures that ISPs can take to fulfil their responsibility to respect the right to privacy. It utilizes the challenges to the right to privacy to discuss some aspects of the extension of human rights responsibilities to corporations. These include the respective roles of government and non-state actors, the extent to which corporations may be required to act proactively in order to protect the privacy of clients, and the relevance of transnational activity.

  3. 29 CFR 37.35 - What are a recipient's responsibilities to provide services and information in languages other...

    Science.gov (United States)

    2010-07-01

    ... and information in languages other than English? 37.35 Section 37.35 Labor Office of the Secretary of... Communication § 37.35 What are a recipient's responsibilities to provide services and information in languages... services or information in a language other than English in order to be effectively informed about, or able...

  4. The influence of leptin on Th1/Th2 balance in obese children with asthma

    Directory of Open Access Journals (Sweden)

    Doaa Mohammed Youssef

    2013-09-01

    Full Text Available OBJECTIVE: In individuals with asthma, obesity induces the production of leptin and is associated with disease severity. Our objective was to evaluate the levels of serum leptin and their effect on Th1/Th2 balance in obese and non-obese children with asthma, as well as to investigate the association between serum leptin levels and clinical outcomes. METHODS: We evaluated 50 atopic children with physician-diagnosed moderate-to-severe persistent asthma and 20 controls. The children with asthma were divided into two groups, by body mass index percentile: obese (n = 25 and non-obese (n = 25. From all subjects, we collected peripheral blood samples in order to determine the levels of leptin, IFN-γ, and IL-4. Asthma severity was assessed by an asthma symptom score, and the results were correlated with the parameters studied. RESULTS: Serum leptin levels were significantly higher in the obese asthma group than in the non-obese asthma group, as well as being significantly higher in the children with asthma than in the controls, whereas IFN-γ levels were significantly higher and IL-4 levels were significantly lower in the obese asthma group than in the non-obese asthma group. In addition, the obese asthma group showed higher asthma symptom scores and significantly lower FEV1 (% of predicted than did the non-obese asthma group. There was a significant positive correlation between leptin and IFN-γ levels only in the obese asthma group. CONCLUSIONS: Although leptin is involved in the pathogenesis of asthma in obese and non-obese children, its effect is more pronounced in the former. In the presence of high leptin levels, only obese children with asthma exhibited Th1 polarization, with higher IFN-γ levels and greater asthma severity.

  5. Does unrestrained single-chamber plethysmography provide a valid assessment of airway responsiveness in allergic BALB/c mice?

    Directory of Open Access Journals (Sweden)

    Chen Guoqin

    2009-07-01

    Full Text Available Abstract Background Unrestrained plethysmography has been used to monitor bronchoconstriction because of its ease of use and ability to measure airway responsiveness in conscious animals. However, its reliability remains controversial. Objective To investigate if unrestrained plethysmography could provide a valid interpretation of airway responsiveness in allergic BALB/c mice. Methods Ovalbumin sensitized BALB/c mice were randomized to receive either a single-dose Ovalbumin challenge (OVA-1D group or a three-dose Ovalbumin challenge (OVA-3D group. The OVA-1D group was further divided into OVA-1D-I (measured invasively, using lung resistance as the index of responsiveness and OVA-1D-N group (measured non-invasively, using Penh as the index of responsiveness. Similarly the OVA-3D group was divided into OVA-3D-I and OVA-3D-N groups based on the above methods. The control groups were sensitized and challenged with normal saline. Bronchial alveolar lavage fluid was taken and airway histopathology was evaluated for airway inflammation. Nasal responsiveness was tested with histamine challenge. Results Compared with controls, a significant increase in airway responsiveness was shown in the OVA-1D-N group (P Conclusion Penh can not be used as a surrogate for airway resistance. The invasive measurement is specific to lower airway. Penh measurement (done as a screening procedure, must be confirmed by a direct invasive measurement specific to lower airway in evaluating lower airway responsiveness.

  6. Involvement of the Th1 subset of CD4+ T cells in acquired immunity to mouse infection with Trypanosoma equiperdum.

    Science.gov (United States)

    Perito, S; Calabresi, A; Romani, L; Puccetti, P; Bistoni, F

    1992-09-01

    Heat- or merthiolate-inactivated Trypanosoma equiperdum was administered to recipient mice that were subsequently challenged with viable inocula of the same stabilate. Only mice inoculated with merthiolate-killed parasites were completely protected from a challenge inoculum of 10(3) trypanosomes, an effect that was abolished by prior immunosuppression of mice. Immune sera from protected animals contained high levels of interferon (IFN)-gamma and specific IgG2a antibodies. Spleen cells from these mice produced high amounts of interleukin (IL)-2 and IFN-gamma in vitro in response to specific antigen or concanavalin A, whereas splenocytes from mice receiving heat-killed parasites produced high amounts of IL-6. In contrast, the production of tumor necrosis factor (TNF)-alpha and colony-stimulating activity (CSA) was not significantly different in mice receiving either killed parasite preparation. The protection in immunized mice was associated with the detection of strong delayed-type hypersensitivity (DTH) to T. equiperdum antigens, an effect that could be adoptively transferred onto naive recipients by specifically immune CD4+ lymphocytes. These results suggest that the development of protective immunity in mice to T. equiperdum by our immunization protocol may involve the activity of helper/DTH T cells, particularly those of the Th1 subset.

  7. Comprehensive Profiling of Immune Responses in MARV Survivors Demonstrates Robust Th1-Skewing with Short Lived Neutralizing Antibody Responses

    Science.gov (United States)

    2017-03-29

    unprecedented scale, spanning two years and infecting more than 28,000 individuals. Previously, the largest filovirus outbreaks had numbered in the tens to...virus (BDBV) have all caused outbreaks that numbered over 100 cases – twice, in the cases of MARV and SUDV. EBOV may garner much of the attention , but

  8. DC microgrids with energy storage systems and demand response for providing support to frequency regulation of electrical power systems

    DEFF Research Database (Denmark)

    Basic, Hrvoje; Dragicevic, Tomislav; Pandzic, Hrvoje

    2017-01-01

    Frequency regulation of electric power systems efficiency depends on response time and on power reserves for frequency regulation. As integration of non-dispatchable renewable generation in the power system results with increased need for power reserves from fast responding power units, the idea...... of using aggregated DC microgrids in frequency regulation is presented. Model proposed in this work is based on using battery energy storage, combined with demand response for achieving efficient usage of battery energy storage. It is shown that large number of DC microgrids can provide sufficient....

  9. Taxonomic and functional diversity provides insight into microbial pathways and stress responses in the saline Qinghai Lake, China.

    Directory of Open Access Journals (Sweden)

    Qiuyuan Huang

    Full Text Available Microbe-mediated biogeochemical cycles contribute to the global climate system and have sensitive responses and feedbacks to environmental stress caused by climate change. Yet, little is known about the effects of microbial biodiversity (i.e., taxonmic and functional diversity on biogeochemical cycles in ecosytems that are highly sensitive to climate change. One such sensitive ecosystem is Qinghai Lake, a high-elevation (3196 m saline (1.4% lake located on the Tibetan Plateau, China. This study provides baseline information on the microbial taxonomic and functional diversity as well as the associated stress response genes. Illumina metagenomic and metatranscriptomic datasets were generated from lake water samples collected at two sites (B and E. Autotrophic Cyanobacteria dominated the DNA samples, while heterotrophic Proteobacteria dominated the RNA samples at both sites. Photoheterotrophic Loktanella was also present at both sites. Photosystem II was the most active pathway at site B; while, oxidative phosphorylation was most active at site E. Organisms that expressed photosystem II or oxidative phosphorylation also expressed genes involved in photoprotection and oxidative stress, respectively. Assimilatory pathways associated with the nitrogen cycle were dominant at both sites. Results also indicate a positive relationship between functional diversity and the number of stress response genes. This study provides insight into the stress resilience of microbial metabolic pathways supported by greater taxonomic diversity, which may affect the microbial community response to climate change.

  10. The Effectiveness of Emergency Response System’s Service Providers for Road Accidents in Johor Bahru, Malaysia

    Directory of Open Access Journals (Sweden)

    Kazunori H.

    2012-01-01

    Full Text Available In Malaysia, there are three core services involved in emergency, namely the fire and rescue, police, and ambulance services. The aim of the service providers is to prevent the loss of life and damage by improving their response time. The Civil Defence Department and the 999 call centre also assist the main providers. This paper aims to provide an overview of emergency response system (ERS for road accidents in Johor Bahru. The objective is to find the effective services from ERS works. There are three sections of chronological events involved: the call centre receiving reports on accidents, at location of the accident and the time during which the victims are brought to the hospital. The paper studies the operation scheme of the ERS by describing the condition; to analyse the questionnaire using a set of questions on the ERS service; and to determine the effectiveness of the services provided. The provider’s services can be identified as a main factor in improving the ERS services provided in the study area.

  11. Differential Proteomic Profiles of Pleurotus ostreatus in Response to Lignocellulosic Components Provide Insights into Divergent Adaptive Mechanisms.

    Science.gov (United States)

    Xiao, Qiuyun; Ma, Fuying; Li, Yan; Yu, Hongbo; Li, Chengyun; Zhang, Xiaoyu

    2017-01-01

    Pleurotus ostreatus is a white rot fungus that grows on lignocellulosic biomass by metabolizing the main constituents. Extracellular enzymes play a key role in this process. During the hydrolysis of lignocellulose, potentially toxic molecules are released from lignin, and the molecules are derived from hemicellulose or cellulose that trigger various responses in fungus, thereby influencing mycelial growth. In order to characterize the mechanism underlying the response of P. ostreatus to lignin, we conducted a comparative proteomic analysis of P. ostreatus grown on different lignocellulose substrates. In this work, the mycelium proteome of P. ostreatus grown in liquid minimal medium with lignin, xylan, and carboxymethyl cellulose (CMC) was analyzed using the complementary two-dimensional gel electrophoresis (2-DE) approach; 115 proteins were identified, most of which were classified into five types according to their function. Proteins with an antioxidant function that play a role in the stress response were upregulated in response to lignin. Most proteins involving in carbohydrate and energy metabolism were less abundant in lignin. Xylan and CMC may enhanced the process of carbohydrate metabolism by regulating the level of expression of various carbohydrate metabolism-related proteins. The change of protein expression level was related to the adaptability of P. ostreatus to lignocellulose. These findings provide novel insights into the mechanisms underlying the response of white-rot fungus to lignocellulose.

  12. Quantitative Phosphoproteomic Analysis Provides Insight into the Response to Short-Term Drought Stress in Ammopiptanthus mongolicus Roots

    Directory of Open Access Journals (Sweden)

    Huigai Sun

    2017-10-01

    Full Text Available Drought is one of the major abiotic stresses that negatively affects plant growth and development. Ammopiptanthus mongolicus is an ecologically important shrub in the mid-Asia desert region and used as a model for abiotic tolerance research in trees. Protein phosphorylation participates in the regulation of various biological processes, however, phosphorylation events associated with drought stress signaling and response in plants is still limited. Here, we conducted a quantitative phosphoproteomic analysis of the response of A. mongolicus roots to short-term drought stress. Data are available via the iProx database with project ID IPX0000971000. In total, 7841 phosphorylation sites were found from the 2019 identified phosphopeptides, corresponding to 1060 phosphoproteins. Drought stress results in significant changes in the abundance of 103 phosphopeptides, corresponding to 90 differentially-phosphorylated phosphoproteins (DPPs. Motif-x analysis identified two motifs, including [pSP] and [RXXpS], from these DPPs. Functional enrichment and protein-protein interaction analysis showed that the DPPs were mainly involved in signal transduction and transcriptional regulation, osmotic adjustment, stress response and defense, RNA splicing and transport, protein synthesis, folding and degradation, and epigenetic regulation. These drought-corresponsive phosphoproteins, and the related signaling and metabolic pathways probably play important roles in drought stress signaling and response in A. mongolicus roots. Our results provide new information for understanding the molecular mechanism of the abiotic stress response in plants at the posttranslational level.

  13. Multiparameter fluorescence imaging for quantification of TH-1 and TH-2 cytokines at the single-cell level

    Science.gov (United States)

    Fekkar, Hakim; Benbernou, N.; Esnault, S.; Shin, H. C.; Guenounou, Moncef

    1998-04-01

    Immune responses are strongly influenced by the cytokines following antigenic stimulation. Distinct cytokine-producing T cell subsets are well known to play a major role in immune responses and to be differentially regulated during immunological disorders, although the characterization and quantification of the TH-1/TH-2 cytokine pattern in T cells remained not clearly defined. Expression of cytokines by T lymphocytes is a highly balanced process, involving stimulatory and inhibitory intracellular signaling pathways. The aim of this study was (1) to quantify the cytokine expression in T cells at the single cell level using optical imaging, (2) and to analyze the influence of cyclic AMP- dependent signal transduction pathway in the balance between the TH-1 and TH-2 cytokine profile. We attempted to study several cytokines (IL-2, IFN-(gamma) , IL-4, IL-10 and IL-13) in peripheral blood mononuclear cells. Cells were prestimulated in vitro using phytohemagglutinin and phorbol ester for 36h, and then further cultured for 8h in the presence of monensin. Cells were permeabilized and then simple-, double- or triple-labeled with the corresponding specific fluorescent monoclonal antibodies. The cell phenotype was also determined by analyzing the expression of each of CD4, CD8, CD45RO and CD45RA with the cytokine expression. Conventional images of cells were recorded with a Peltier- cooled CCD camera (B/W C5985, Hamamatsu photonics) through an inverted microscope equipped with epi-fluorescence (Diaphot 300, Nikon). Images were digitalized using an acquisition video interface (Oculus TCX Coreco) in 762 by 570 pixels coded in 8 bits (256 gray levels), and analyzed thereafter in an IBM PC computer based on an intel pentium processor with an adequate software (Visilog 4, Noesis). The first image processing step is the extraction of cell areas using an edge detection and a binary thresholding method. In order to reduce the background noise of fluorescence, we performed an opening

  14. Leishmania donovani-reactive Th1- and Th2-like T-cell clones from individuals who have recovered from visceral leishmaniasis

    DEFF Research Database (Denmark)

    Kemp, M; Kurtzhals, J A; Bendtzen, K

    1993-01-01

    Infections in humans by Leishmania donovani parasites can result in a fatal disease, visceral leishmaniasis (VL), or in a self-limiting asymptomatic infection. In murine models of the infection employing Leishmania major, the course of the disease can be directed into a VL-like syndrome by interl......Infections in humans by Leishmania donovani parasites can result in a fatal disease, visceral leishmaniasis (VL), or in a self-limiting asymptomatic infection. In murine models of the infection employing Leishmania major, the course of the disease can be directed into a VL-like syndrome...... only IFN-gamma. This is the first report of a Th1- and Th2-type response in human leishmaniasis. These results suggest that in analogy with murine models, there is a dichotomy in the human T-cell response to L. donovani infections. Preferential activation of IL-4-producing Th2-like cells may...... be involved in the exacerbation of human VL, whereas activation of IFN-gamma-producing Th1 cells may protect the host from severe disease. Identification of leishmanial antigens activating one or the other type of T cells will be important in the development of vaccines against leishmaniasis....

  15. An Application of Narrowing the Information Gap Between Data Providers and Decision Makers Through a Disaster Response Scenario

    Science.gov (United States)

    Lowther, R. P.; Brill, M.

    2008-12-01

    A scenario-based distributed information system for operationally building the Global Earth Observing System of Systems (GEOSS) is presented as part of Northrop Grumman's participation in the GEOSS ten- year Architecture Implementation Pilot plan. Northrop Grumman is responding to the application challenge of implementing GEOSS capabilities by adding several U.S. Global Earth Observing (USGEO) data providers through architecture development and multiple scenario demonstrations, one of which is Natural Disaster Response. The scenarios ensure responders collaborate with the Group on Earth Observations (GEO) Societal Benefit Area working groups and external agencies. A six-stage disaster cycle is executed for a major hurricane and flooding scenario on the Port of Houston that incorporates multiple user communities and demonstrates how communities of practice may be applied to extend information sharing in response to disasters. The scenario is user driven and uses products derived from existing earth observing systems. The enterprise model for this hurricane and flooding scenario depicts an end-to-end approach to executing disaster response management. The centrality of the community portal in creating a coordinated disaster response cannot be overstated. Northrop Grumman has reached interoperability agreements with multiple community data providers whose goal is to make their data and products accessible as "persistent exemplars" within GEOSS to global users and decision makers. As multiple GEO community members integrate their data and services into GEOSS, the whole of GEOSS becomes much more than the sum of its components; however, GEOSS must deliver high-value information easily understood by decision makers through smart source selection. When this occurs, and GEOSS becomes operational, the information gap will narrow between systems, providers, analysts, and decision makers.

  16. Preferential Th1 cytokine profile of phosphoantigen-stimulated human Vγ9Vδ2 T cells.

    LENUS (Irish Health Repository)

    Dunne, Margaret R

    2010-01-01

    Human Vγ9Vδ2 T cells recognise pyrophosphate-based antigens (phosphoantigens) and have multiple functions in innate and adaptive immunity, including a unique ability to activate other cells of the immune system. We used flow cytometry and ELISA to define the early cytokine profiles of Vγ9Vδ2 T cells stimulated in vitro with isopentenyl pyrophosphate (IPP) and (E)-4-hydroxy-3-methyl-but-2 enyl pyrophosphate (HMB-PP) in the absence and presence of IL-2 and IL-15. We show that fresh Vγ9Vδ2 T cells produce interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) within 4 hours of stimulation with phosphoantigen, but neither IL-10, IL-13, nor IL-17 was detectable up to 72 hours under these conditions. Cytokine production was not influenced by expression or lack, thereof, of CD4 or CD8. Addition of IL-2 or IL-15 caused expansion of IFN-γ-producing Vγ9Vδ2 T cells, but did not enhance IFN-γ secretion after 24-72 hours. Thus, phosphoantigen-stimulated Vγ9Vδ2 T cells have potential as Th1-biasing adjuvants for immunotherapy.

  17. Th1 and Th2-like protein balance in human inflammatory radicular cysts and periapical granulomas.

    Science.gov (United States)

    de Carvalho Fraga, Carlos Alberto; Alves, Lucas Rodrigues; de Sousa, Adriana Alkmim; de Jesus, Sabrina Ferreira; Vilela, Daniel Nogueira; Pereira, Camila Santos; Batista Domingos, Patrícia Luciana; Viana, Agostinho Gonçalves; Jham, Bruno Correia; Batista de Paula, Alfredo Maurício; Sena Guimarães, André Luiz

    2013-04-01

    Chronic dental periapical lesions result from chronic inflammation of periapical tissues caused by continuous antigenic stimulation from infected root canals. Recent findings have suggested that T helper (Th) 1 and Th2-like cytokines are important in the pathogenesis of chronic periapical inflammatory diseases. However, the mechanisms regulating these immunoinflammatory pathways have not been fully elucidated. Thus, the aim of this study was to evaluate interleukin (IL)-4, IL-12, and interferon γ (IFN-γ) protein levels in human radicular cysts and periapical granulomas. Archived samples of cysts (n = 52) and granulomas (n = 27) were sectioned and submitted to immunohistochemistry to evaluate the tissue expression of IL-4, IL-12, and IFN-γ. The data were analyzed using the Mann-Whitney U test (P radicular cysts. IL-4 expression was stronger in periapical granulomas than in radicular cysts. IL-12 was not detected in any of the samples. Our study showed that IFN-γ protein levels are increased in radicular cysts, whereas IL-4 expression is stronger in samples of periapical granulomas. Further studies are necessary to elucidate the signaling pathways mediated by these cytokines and to facilitate the development of more effective periapical disease management strategies. Copyright © 2013 American Association of Endodontists. All rights reserved.

  18. Cytotoxic Th1 and Th17 cells infiltrate the intestinal mucosa of Behcet patients and exhibit high levels of TNF-α in early phases of the disease

    Science.gov (United States)

    Emmi, Giacomo; Silvestri, Elena; Bella, Chiara Della; Grassi, Alessia; Benagiano, Marisa; Cianchi, Fabio; Squatrito, Danilo; Cantarini, Luca; Emmi, Lorenzo; Selmi, Carlo; Prisco, Domenico; D’Elios, Mario Milco

    2016-01-01

    Abstract Background: Gastrointestinal involvement is one of the most serious in Behçet disease, potentially leading to severe complications. Aim of this study was to investigate at mucosal level the T-cell responses in Behçet patients with early intestinal involvement. Methods: We isolated T cells from intestinal mucosa of 8 patients with intestinal symptoms started within 6 months. T lymphocytes were cloned and analyzed for surface phenotype and cytokines production. Results: We obtained 382 T-cell clones: 324 were CD4+ and 58 were CD8+. Within the 324 CD4+ clones, 195 were able to secrete IFN-γ and TNF-α, but not IL-4, nor IL-17 thus showing a polarized Th1 profile, whereas CD4 clones producing both IFN-γ and IL-17 (Th1/Th17 profile) were 79. Likewise, the number of CD8 clones producing type 1 cytokines was higher than those of CD8 clones producing both type 1 and 2 cytokines. Almost all intestinal-derived T-cell clones expressed perforin-mediated cytotoxicity and Fas–Fas Ligand-mediated pro-apoptotic activity. Conclusions: Our results indicate that in the early stages of the disease, both Th1 and Th17 cells drive inflammation leading to mucosal damage via abnormal and long-lasting cytokines production as well as via both perforin- and Fas–Fas ligand-mediated cytotoxicity. Finally, all the T cells at mucosal level were able to produce large amount of TNF-α, suggesting that its production is a property of intestinal T cells of patients with early active intestinal disease. These results support the therapy with anti-TNF-α agents and suggest the use of anti-IL-17 monoclonal antibodies in Behçet patients with early intestinal involvement. PMID:27930541

  19. The Relationship between the Antitumor Effect of the IL-12 Gene Therapy and the Expression of Th1 Cytokines in an HPV16-Positive Murine Tumor Model

    Directory of Open Access Journals (Sweden)

    Flor García Paz

    2014-01-01

    Full Text Available Objective. The goal of the present study was to investigate the effect of IL-12 expressed in plasmid on the Th1 cytokine profile in an experimental HPV16-positive murine tumor model and the association with the IL-12’s antitumor effect. Methods. Mice were injected with BMK-16/myc cells to establish HPV16-positive tumor and then pNGVL3-mIL-12 plasmid; pcDNA3 plasmid or PBS was injected directly into tumor site. The antitumor effect of the treatment was evaluated and the cytokines expression profile in each tumor tissue was analyzed. Results. Treatment with pNGVL3-mIL-12 plasmid had a significant antitumor effect, and a Th2-Th3-type cytokines prolife was detected in the murine tumor model with expression of the cytokines IL-10, IL-4, and TGF-β1. However, after the tumor was treated with three intratumoral injections of plasmid containing IL-12 cDNA, it showed a cytokine profile associated with Th1 with expression of IL-2, IL-12, and IFN-γ cytokines and reduced expression of IL-10, IL-4, and TGF-β1. Conclusions. The treatment with the IL-12 gene in the experimental HPV16-positive tumor model promoted the activation of the cellular immune response via expression of a Th1-type cytokine profile and was associated with the inhibition of tumor growth. Thus, IL-12 treatment represents a novel approach for gene therapy against cervical cancer.

  20. A novel respiratory syncytial virus (RSV F subunit vaccine adjuvanted with GLA-SE elicits robust protective TH1-type humoral and cellular immunity in rodent models.

    Directory of Open Access Journals (Sweden)

    Stacie L Lambert

    Full Text Available Illness associated with Respiratory Syncytial Virus (RSV remains an unmet medical need in both full-term infants and older adults. The fusion glycoprotein (F of RSV, which plays a key role in RSV infection and is a target of neutralizing antibodies, is an attractive vaccine target for inducing RSV-specific immunity.BALB/c mice and cotton rats, two well-characterized rodent models of RSV infection, were used to evaluate the immunogenicity of intramuscularly administered RSV vaccine candidates consisting of purified soluble F (sF protein formulated with TLR4 agonist glucopyranosyl lipid A (GLA, stable emulsion (SE, GLA-SE, or alum adjuvants. Protection from RSV challenge, serum RSV neutralizing responses, and anti-F IgG responses were induced by all of the tested adjuvanted RSV sF vaccine formulations. However, only RSV sF + GLA-SE induced robust F-specific TH1-biased humoral and cellular responses. In mice, these F-specific cellular responses include both CD4 and CD8 T cells, with F-specific polyfunctional CD8 T cells that traffic to the mouse lung following RSV challenge. This RSV sF + GLA-SE vaccine formulation can also induce robust RSV neutralizing titers and prime IFNγ-producing T cell responses in Sprague Dawley rats.These studies indicate that a protein subunit vaccine consisting of RSV sF + GLA-SE can induce robust neutralizing antibody and T cell responses to RSV, enhancing viral clearance via a TH1 immune-mediated mechanism. This vaccine may benefit older populations at risk for RSV disease.

  1. Intercellular adhesion molecule 1 mediates migration of Th1 and Th17 cells across human retinal vascular endothelium.

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    Bharadwaj, Arpita S; Schewitz-Bowers, Lauren P; Wei, Lai; Lee, Richard W J; Smith, Justine R

    2013-10-23

    Autoimmune inflammation of the retina causes vision loss in the majority of affected individuals. Th1 or Th17 cells initiate the disease on trafficking from the circulation into the eye across the retinal vascular endothelium. We investigated the ability of human Th1- and Th17-polarized cells to cross a simulated human retinal endothelium, and examined the role of IgG superfamily members in this process. Th1- and Th17-polarized cell populations were generated from human peripheral blood CD4(+) T cells, using two Th1- and Th17-polarizing protocols. Transendothelial migration assays were performed over 18 hours in Boyden chambers, after seeding the transwell membrane with human retinal endothelial cells. In some assays intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), or activated leukocyte cell adhesion molecule (ALCAM) blocking antibody, or isotype- and concentration-matched control antibody, was added to the upper chambers. Th1- and Th17-polarized cells migrated equally efficiently across the human retinal endothelial monolayer. The percentage of IL-17(+) IFN-γ(-) Th17-polarized cells was reduced following migration. Blocking ICAM-1, but not VCAM-1 or ALCAM, significantly reduced migration of Th1- and Th17-polarized cells for a majority of human donors. Taken in the context of other literature on transendothelial migration, our results illustrate the importance of investigating the specific tissue and vascular endothelium when considering helper T cell migration in autoimmune inflammation. Our findings further indicate that while generalizations about involvement of specific adhesion molecules in uveitis and other autoimmune disease may be possible, these may not apply to individual patients universally. The observations are relevant to the use of adhesion blockade for therapeutic purposes.

  2. Immunomodulatory effects of Pseudostellaria heterophylla (Miquel) Pax on regulation of Th1/Th2 levels in mice with atopic dermatitis.

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    Choi, You Yeon; Kim, Mi Hye; Ahn, Kwang Seok; Um, Jae-Young; Lee, Seok-Geun; Yang, Woong Mo

    2017-02-01

    Pseudostellaria heterophylla (PH) has various pharmacological effects that include immunologic enhancement and anti‑oxidation. However, it remains unclear whether PH exerts beneficial effects in dermatological diseases. The present study examined the effects of PH on a 2,4-dinitrochlorobenzene (DNCB)‑induced atopic dermatitis (AD) mouse model and elucidated its underlying mechanism of action. PH extract (1 and 100 mg/ml) was applied topically to DNCB-treated dorsal skin of mice every day for 11 days. The immunomodulatory effects of PH were evaluated by measuring skin thickness, mast cell infiltration, serum levels of immunoglobulin E (IgE), and mRNA expression levels of T helper (h)1/Th2 and pro‑inflammatory cytokines in dorsal skin. In addition, cluster of differentiation (CD)4+ T cells were detected in dorsal skin by immunohistochemistry. Topical application of PH significantly reduced the thickness of dermis, epidermis and serum IgE production compared with the DNCB group. PH treatment inhibited infiltration of inflammatory cells, including mast cells and CD4+ T cells, and suppressed the mRNA expression levels of cytokines (interferon‑γ, interleukin‑4, ‑6, ‑8 and ‑1β, and tumor necrosis factor‑α) associated with the immune response. Furthermore, PH treatment significantly downregulated the protein expression levels of nuclear factor‑κB, phosphorylated inhibitor of κBα and mitogen‑activated protein kinases. The results suggested that PH may be a potential therapeutic strategy for the treatment of AD via the modulation of Th1 and Th2 levels.

  3. Inactivated Parapoxvirus ovis induces a transient increase in the expression of proinflammatory, Th1-related, and autoregulatory cytokines in mice

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    Anziliero, D.; Weiblen, R. [Setor de Virologia, Departamento de Medicina Veterinária Preventiva, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil, Setor de Virologia, Departamento de Medicina Veterinária Preventiva, Universidade Federal de Santa Maria, Santa Maria, RS (Brazil); Kreutz, L.C. [Programa de Pós-Graduação em Bioexperimentação, Faculdade de Agronomia e Medicina Veterinária, Universidade de Passo Fundo, Passo Fundo, RS, Brasil, Programa de Pós-Graduação em Bioexperimentação, Faculdade de Agronomia e Medicina Veterinária, Universidade de Passo Fundo, Passo Fundo, RS (Brazil); Spilki, F. [Laboratório de Microbiologia Molecular, Instituto de Ciências da Saúde, Universidade Feevale, Novo Hamburgo, RS, Brasil, Laboratório de Microbiologia Molecular, Instituto de Ciências da Saúde, Universidade Feevale, Novo Hamburgo, RS (Brazil); Flores, E.F. [Setor de Virologia, Departamento de Medicina Veterinária Preventiva, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil, Setor de Virologia, Departamento de Medicina Veterinária Preventiva, Universidade Federal de Santa Maria, Santa Maria, RS (Brazil)

    2014-02-17

    The immunostimulatory properties of inactivated Parapoxvirus ovis (iPPVO) have long been investigated in different animal species and experimental settings. In this study, we investigated the effects of iPPVO on cytokine expression in mice after intraperitoneal inoculation. Spleen and sera collected from iPPVO-treated mice at intervals after inoculation were submitted to cytokine mRNA determination by real-time PCR (qPCR), serum protein concentration by ELISA, and interferon (IFN)-α/β activity by bioassay. The spleen of iPPVO-treated animals showed a significant increase in mRNA expression of all cytokines assayed, with different kinetics and magnitude. Proinflammatory cytokines interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), and IL-8 mRNA peaked at 24 hours postinoculation (hpi; 5.4-fold increase) and 48 hpi (3- and 10-fold increases), respectively. A 15-fold increase in IFN-γ and 6-fold IL-12 mRNA increase were detected at 48 and 24 hpi, respectively. Increased expression of autoregulatory cytokines (Th2), mainly IL-10 and IL-4, could be detected at later times (72 and 96 hpi) with peaks of 4.7- and 4.9-fold increases, respectively. IFN-I antiviral activity against encephalomyocarditis virus was demonstrated in sera of treated animals between 6 and 12 hpi, with a >90% reduction in the number of plaques. Measurement of serum proteins by ELISA revealed increased levels of IL-1, TNF-α, IL-12, IFN-γ, and IL-10, with kinetics similar to those observed by qPCR, especially for IL-12 and IFN-γ. These data demonstrate that iPPVO induced a transient and complex cytokine response, initially represented by Th1-related cytokines followed by autoregulatory and Th2 cytokines.

  4. Anisakis simplex allergy: a murine model of anaphylaxis induced by parasitic proteins displays a mixed Th1/Th2 pattern

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    Baeza, M L; Conejero, L; Higaki, Y; Martín, E; Pérez, C; Infante, S; Rubio, M; Zubeldia, J M

    2005-01-01

    The study of the singular hypersensitivity reactions to Anisakis simplex (A.s) proteins, may help us to undestand many of the unknown immune interactions between helmiths infections and allergy. We have developed a murine model of allergy to A. simplex, that mimics human A. simplex allergy to study the specific aspects of anaphylaxis induced by parasites. Male C3H/HeJ mice were intraperitoneally sensitized to A. simplex. Mice were then intravenous or orally challenged with A. simplex. Antigen-specific immunoglobulins, polyclonal IgE, anaphylactic symptoms, plasma histamine levels and cytokine profiles were determined. Comparative IgE immunoblot analyses were also performed. Specific IgE, IgG1 and IgG2a were detected in sensitized mice since week 3. Polyclonal IgE raised and peaked with different kinetics. Intravenous A. simplex challenge produced anaphylaxis in mice, accompanied by plasma histamine release. Oral A. simplex challenge in similarly sensitized mice did not caused symptoms nor histamine release. Numerous A. simplex allergens were recognized by sensitized mouse sera, some of them similar to human serum. The A. simplex stimulated splenocytes released IL-10, IFN-γ, IL-4, IL-13 and IL-5. We describe a new animal model of anaphylaxis. It exhibits characteristics of type I hypersensitivity reactions to Anisakis simplex similar to those observed in allergic humans. Different responses to i.v. or oral A. simplex challenges emerged, which did not reflect a window tolerization period. The cytokine profile developed (mixed Th1/Th2 pattern) differed from the observed in classical models of anaphylaxis or allergy to food antigens. This model may permit to investigate the peculiar allergic reactions to parasitic proteins. PMID:16297154

  5. Opening Minds Stigma Scale for Health Care Providers (OMS-HC): Examination of psychometric properties and responsiveness

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    2014-01-01

    Background Diminishing stigmatization for those with mental illnesses by health care providers (HCPs) is becoming a priority for programming and policy, as well as research. In order to be successful, we must accurately measure stigmatizing attitudes and behaviours among HCPs. The Opening Minds Stigma Scale for Health Care Providers (OMS-HC) was developed to measure stigma in HCP populations. In this study we revisit the factor structure and the responsiveness of the OMS-HC in a larger, more representative sample of HCPs that are more likely to be targets for anti-stigma interventions. Methods Baseline data were collected from HCPs (n = 1,523) during 12 different anti-stigma interventions across Canada. The majority of HCPs were women (77.4%) and were either physicians (MDs) (41.5%), nurses (17.0%), medical students (13.4%), or students in allied health programs (14.0%). Exploratory factor analysis (EFA) was conducted using complete pre-test (n = 1,305) survey data and responsiveness to change analyses was examined with pre and post matched data (n = 803). The internal consistency of the OMS-HC scale and subscales was evaluated using the Cronbach’s alpha coefficient. The scale’s sensitivity to change was examined using paired t-tests, effect sizes (Cohen’s d), and standardized response means (SRM). Results The EFA favored a 3-factor structure which accounted for 45.3% of the variance using 15 of 20 items. The overall internal consistency for the 15-item scale (α = 0.79) and three subscales (α = 0.67 to 0.68) was acceptable. Subgroup analysis showed the internal consistency was satisfactory across HCP groups including physicians and nurses (α = 0.66 to 0.78). Evidence for the scale’s responsiveness to change occurred across multiple samples, including student-targeted interventions and workshops for practicing HCPs. The Social Distance subscale had the weakest level of responsiveness (SRM ≤ 0.50) whereas the more attitudinal

  6. Acute ethanol treatment upregulates th1, th2 and hdc in larval zebrafish in stable networks

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    Henri ePuttonen

    2013-05-01

    Full Text Available Earlier studies in zebrafish have revealed that acutely given ethanol has a stimulatory effect on locomotion in fish larvae but the mechanism of this effect has not been revealed. We studied the effects of ethanol concentrations between 0.75% and 3.00% on 7-day-old larval zebrafish (Danio rerio of the Turku strain. At 0.75-3% concentrations ethanol increased swimming speed during the first minute. At 3% the swimming speed decreased rapidly after the first minute, whereas at 0.75 and 1.5% a prolonged increase in swimming speed was seen. At the highest ethanol concentration dopamine levels decreased significantly after a 10-min treatment. We found that ethanol upregulates key genes involved in the biosynthesis of histamine (hdc and dopamine (th1 and th2 following a short 10-min ethanol treatment, measured by qPCR. Using in situ hybridisation and immunohistochemistry, we further discovered that the morphology of the histaminergic and dopaminergic neurons and networks in the larval zebrafish brain was unaffected by both the 10-min and a longer 30-min treatment. The results suggest that acute ethanol rapidly decreases dopamine levels, and activates both forms or th to replenish the dopamine stores within 30 minutes. The dynamic changes in histaminergic and dopaminergic system enzymes occured in the same cells which normally express the transcripts. As both dopamine and histamine are known to be involved in the behavioural effects of ethanol and locomotor stimulation, these results suggest that rapid adaptations of these networks are associated with altered locomotor activity.

  7. Continuous and Discontinuous Cigarette Smoke Exposure Differentially Affects Protective Th1 Immunity against Pulmonary Tuberculosis

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    Shaler, Christopher R.; Horvath, Carly N.; McCormick, Sarah; Jeyanathan, Mangalakumari; Khera, Amandeep; Zganiacz, Anna; Kasinska, Joanna; Stampfli, Martin R.; Xing, Zhou

    2013-01-01

    Pulmonary tuberculosis (TB), caused by Mycobacterium tuberculosis, is the leading cause of death due to a bacterial pathogen. Emerging epidemiologic evidence suggests that the leading risk factor associated with TB mortality is cigarette smoke exposure. Despite this, it remains poorly understood what is the effect of cigarette smoke exposure on anti-TB immunity and whether its potential detrimental effect can be reversed by cigarette smoking cessation. In our current study, we have investigated the impact of both continuous and discontinuous cigarette smoke exposure on the development of anti-mycobacterial type 1 immunity in murine models. We find that while continuous cigarette smoke exposure severely impairs type 1 immunity in the lung, a short-term smoking cessation allows rapid restoration of anti-mycobacterial immunity. The ability of continuous cigarette smoke exposure to dampen type 1 protective immunity is attributed locally to its affects on innate immune cells in the lung. Continuous cigarette smoke exposure locally, by not systemically, impairs APC accumulation and their production of TNF, IL-12, and RANTES, blunts the recruitment of CD4+IFN-γ+ T cells to the lung, and weakens the formation of granuloma. On the other hand, smoking cessation was found to help restore type 1 immunity by rapidly improving the functionality of lung APCs, enhancing the recruitment of CD4+IFN-γ+ T cells to the lung, and promoting the formation of granuloma. Our study for the first time demonstrates that continuous, but not discontinuous, cigarette smoke exposure severely impedes the lung expression of anti-TB Th1 immunity via inhibiting innate immune activation and lung T cell recruitment. Our findings thus suggest cigarette smoking cessation to be beneficial to the control of pulmonary TB. PMID:23527127

  8. Perspectives on providing good access to dental services for elderly people: patient selection, dentists' responsibility and budget management.

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    Grytten, Jostein; Holst, Dorthe

    2013-06-01

    To suggest a model for organizing and financing dental services for elderly people so that they have good access to services. There are few studies on how dental services for elderly people should be organized and financed. This is surprising if we take into consideration the fact that the proportion of elderly people is growing faster than any other group in the population, and that elderly people have more dental diseases and poorer access to dental services than the rest of the adult population. In several countries, dental services are characterized by private providers who often operate in a market with competition and free price-setting. Private dentists have no community responsibility, and they are free to choose which patients they treat. Literature review and critical reasoning. In order to avoid patient selection, a patient list system for elderly people is recommended, with per capita remuneration for the patients that the dentist is given responsibility for. The patient list system means that the dentist assumes responsibility for a well-defined list of elderly people. Our model will lead to greater security in the dentist/patient relationship, and patients with great treatment needs will be ensured access to dental services. © 2012 John Wiley & Sons A/S and The Gerodontology Society. Published by John Wiley & Sons Ltd.

  9. Transcriptomic analyses on muscle tissues of Litopenaeus vannamei provide the first profile insight into the response to low temperature stress.

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    Wen Huang

    Full Text Available The Pacific white shrimp (Litopenaeus vannamei is an important cultured crustacean species worldwide. However, little is known about the molecular mechanism of this species involved in the response to cold stress. In this study, four separate RNA-Seq libraries of L. vannamei were generated from 13°C stress and control temperature. Total 29,662 of Unigenes and overall of 19,619 annotated genes were obtained. Three comparisons were carried out among the four libraries, in which 72 of the top 20% of differentially-expressed genes were obtained, 15 GO and 5 KEGG temperature-sensitive pathways were fished out. Catalytic activity (GO: 0003824 and Metabolic pathways (ko01100 were the most annotated GO and KEGG pathways in response to cold stress, respectively. In addition, Calcium, MAPK cascade, Transcription factor and Serine/threonine-protein kinase signal pathway were picked out and clustered. Serine/threonine-protein kinase signal pathway might play more important roles in cold adaptation, while other three signal pathway were not widely transcribed. Our results had summarized the differentially-expressed genes and suggested the major important signaling pathways and related genes. These findings provide the first profile insight into the molecular basis of L. vannamei response to cold stress.

  10. Characterization of T cell receptors of Th1 cells infiltrating inflamed skin of a novel murine model of palladium-induced metal allergy.

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    Hiroshi Kobayashi

    Full Text Available Metal allergy is categorized as a delayed-type hypersensitivity reaction, and is characterized by the recruitment of lymphocytes into sites of allergic inflammation. Because of the unavailability of suitable animal models for metal allergy, the role of T cells in the pathogenesis of metal allergy has not been explored. Thus, we developed a novel mouse model for metal allergy associated with infiltration of T cells by multiple injections of palladium (Pd plus lipopolysaccharide into the footpad. Using this model, we characterized footpad-infiltrating T cells in terms of phenotypic markers, T cell receptor (TCR repertoires and cytokine expression. CD3+ CD4+ T cells accumulated in the allergic footpads 7 days after Pd challenge. The expression levels of CD25, interleukin-2, interferon-γ and tumor necrosis factor, but not interleukin-4 and interleukin-5, increased in the footpads after challenge, suggesting CD4+ T helper 1 (Th1 cells locally expanded in response to Pd. Infiltrated T cells in the footpads frequently expressed AV18-1 and BV8-2 T cell receptor (TCR chains compared with T cells in the lymph nodes and exhibited oligoclonality. T-cell clones identified from Pd-allergic mouse footpads shared identical CDR3 sequences containing AV18-1 and BV8-2. These results suggest that TCR AV18-1 and BV8-2 play dominant and critical parts in the antigen specificity of Pd-specific Th1 cells.

  11. C5a regulates IL-12+ DC migration to induce pathogenic Th1 and Th17 cells in sepsis.

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    Ning Ma

    Full Text Available OBJECTIVE: It is well known that complement system C5a is excessively activated during the onset of sepsis. However, it is unclear whether C5a can regulate dentritic cells (DCs to stimulate adaptive immune cells such as Th1 and Th17 in sepsis. METHODS: Sepsis was induced by cecal ligation and puncture (CLP. CLP-induced sepsis was treated with anti-C5a or IL-12. IL-12(+DC, IFNγ(+Th1, and IL-17(+Th17 cells were analyzed by flow cytometry. IL-12 was measured by ELISA. RESULTS: Our studies here showed that C5a induced IL-12(+DC cell migration from the peritoneal cavity to peripheral blood and lymph nodes. Furthermore, IL-12(+DC cells induced the expansion of pathogenic IFNγ(+Th1 and IL-17(+Th17 cells in peripheral blood and lymph nodes. Moreover, IL-12, secreted by DC cells in the peritoneal cavity, is an important factor that prevents the development of sepsis. CONCLUSION: Our data suggests that C5a regulates IL-12(+DC cell migration to induce pathogenic Th1 and Th17 cells in sepsis.

  12. Macromolecular rate theory (MMRT) provides a thermodynamics rationale to underpin the convergent temperature response in plant leaf respiration.

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    Liang, Liyin L; Arcus, Vickery L; Heskel, Mary A; O'Sullivan, Odhran S; Weerasinghe, Lasantha K; Creek, Danielle; Egerton, John J G; Tjoelker, Mark G; Atkin, Owen K; Schipper, Louis A

    2017-10-14

    Temperature is a crucial factor in determining the rates of ecosystem processes, for example, leaf respiration (R) - the flux of plant respired CO2 from leaves to the atmosphere. Generally, R increases exponentially with temperature and formulations such as the Arrhenius equation are widely used in earth system models. However, experimental observations have shown a consequential and consistent departure from an exponential increase in R. What are the principles that underlie these observed patterns? Here, we demonstrate that macromolecular rate theory (MMRT), based on transition state theory (TST) for enzyme-catalyzed kinetics, provides a thermodynamic explanation for the observed departure and the convergent temperature response of R using a global database. Three meaningful parameters emerge from MMRT analysis: the temperature at which the rate of respiration would theoretically reach a maximum (the optimum temperature, Topt ), the temperature at which the respiration rate is most sensitive to changes in temperature (the inflection temperature, Tinf ) and the overall curvature of the log(rate) versus temperature plot (the change in heat capacity for the system, ΔCP‡). On average, the highest potential enzyme-catalyzed rates of respiratory enzymes for R are predicted to occur at 67.0 ± 1.2°C and the maximum temperature sensitivity at 41.4 ± 0.7°C from MMRT. The average curvature (average negative ΔCP‡) was -1.2 ± 0.1 kJ mol(-1)  K(-1) . Interestingly, Topt , Tinf and ΔCP‡ appear insignificantly different across biomes and plant functional types, suggesting that thermal response of respiratory enzymes in leaves could be conserved. The derived parameters from MMRT can serve as thermal traits for plant leaves that represent the collective temperature response of metabolic respiratory enzymes and could be useful to understand regulations of R under a warmer climate. MMRT extends the classic TST to enzyme-catalyzed reactions and provides an

  13. Vitamin D Counteracts Mycobacterium tuberculosis-Induced Cathelicidin Downregulation in Dendritic Cells and Allows Th1 Differentiation and IFNγ Secretion

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    Anna K. O. Rode

    2017-05-01

    Full Text Available Tuberculosis (TB presents a serious health problem with approximately one-third of the world’s population infected with Mycobacterium tuberculosis in a latent state. Experience from the pre-antibiotic era and more recent clinical studies have established a beneficial role of sunlight and vitamin D in patients with TB. At the same time, experimental data have shown that Th1 cells through production of IFNγ are crucial for cathelicidin release by macrophages, bacterial killing, and containment of M. tuberculosis in granulomas. Paradoxically, vitamin D has repeatedly been ascribed an immune-suppressive function inhibiting Th1 differentiation and production of IFNγ in T cells. The aim of this study was to investigate this apparent paradox. We studied naïve human CD4+ T cells activated either with CD3 and CD28 antibodies or with allogeneic dendritic cells (DC stimulated with heat-killed M. tuberculosis (HKMT or purified toll-like receptor (TLR ligands. We show that vitamin D does not block differentiation of human CD4+ T cells to Th1 cells and that interleukin (IL-12 partially counteracts vitamin D-mediated inhibition of IFNγ production promoting production of equal amounts of IFNγ in Th1 cells in the presence of vitamin D as in T cells activated in the absence of vitamin D and IL-12. Furthermore, we show that HKMT and TLR2 ligands strongly downregulate cathelicidin expression in DC and that vitamin D counteracts this by upregulating cathelicidin expression. In conclusion, we demonstrate that vitamin D counteracts M. tuberculosis-induced cathelicidin downregulation and allows Th1 differentiation and IFNγ secretion.

  14. NOD-Like Receptor P3 Inflammasome Controls Protective Th1/Th17 Immunity against Pulmonary Paracoccidioidomycosis

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    Claudia Feriotti

    2017-07-01

    CD8+ T cells expressing IFN-γ and IL-17 whereas those producing IL-4 and TGF-β appeared in increased frequencies. Histopathological studies showed that all deficient mouse strains developed more severe lesions containing elevated numbers of budding yeast cells resulting in increased mortality rates. Altogether, these findings led us to conclude that the activation of the NLRP3 inflammasome has a crucial role in the immunoprotection against pulmonary PCM by promoting the expansion of Th1/Th17 immunity and reducing the suppressive control mediated by Treg cells.

  15. Maternal allergen immunisation to prevent sensitisation in offspring: Th2-polarising adjuvants are more efficient than a Th1-polarising adjuvant in mice

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    Melkild Ingrid

    2010-03-01

    Full Text Available Abstract Background Allergy has been an increasing problem in several parts of the world. Prenatal exposure to allergen and microbial components may affect the development of allergies in childhood, as indicated by epidemiological and experimental studies. We investigated the capacity for allergic sensitisation in offspring after induction of a Th1- or a Th2-polarised immune response to the same allergen in mothers during pregnancy. Results During pregnancy, mice were immunised with ovalbumin (OVA given with either one of the Th2-adjuvants pertussis toxin (PT or Al(OH3 (aluminium hydroxide, or with the Th1 adjuvant CpG. Offspring were immunised with OVA in Al(OH3 as young adults. Serum and supernatants from ex vivo stimulated or non-stimulated spleen cells from mothers and offspring were analysed for OVA-specific antibodies and cytokines, respectively. Mothers immunised with OVA together with either Al(OH3 or PT had increased levels of OVA-specific IgE and IgG1 compared to naive mothers, whereas mothers immunised with OVA together with CpG had increased levels of OVA-specific IgG2a compared to naive mothers. In general the highest levels of IL-5, IL-10, and IFNγ were observed in spleen cells from mothers immunised with PT and OVA. Upon immunisation, offspring from mothers immunised with OVA and either PT or Al(OH3 showed reduced levels of OVA-specific IgE and IgG1 and increased levels of OVA-specific IgG2a antibodies compared to offspring from naive mothers. Maternal immunisation with CpG and OVA did not affect antibody responses in offspring. Conclusion Allergic sensitisation in the offspring was affected by the type of adjuvant used for immunisation of the mothers with the same allergen. Th2 polarisation of the immune response in the mothers was found to give reduced IgE levels upon sensitisation of the offspring, whereas no reduction was achieved with Th1 polarisation in the mothers.

  16. Fourier power, subjective distance and object categories all provide plausible models of BOLD responses in scene-selective visual areas

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    Mark Daniel Lescroart

    2015-11-01

    Full Text Available Perception of natural visual scenes activates several functional areas in the human brain, including the Parahippocampal Place Area (PPA, Retrosplenial Complex (RSC, and the Occipital Place Area (OPA. It is currently unclear what specific scene-related features are represented in these areas. Previous studies have suggested that PPA, RSC, and/or OPA might represent at least three qualitatively different classes of features: (1 2D features related to Fourier power; (2 3D spatial features such as the distance to objects in a scene; or (3 abstract features such as the categories of objects in a scene. To determine which of these hypotheses best describes the visual representation in scene-selective areas, we applied voxel-wise modeling (VM to BOLD fMRI responses elicited by a set of 1,386 images of natural scenes. VM provides an efficient method for testing competing hypotheses by comparing predictions of brain activity based on encoding models that instantiate each hypothesis. Here we evaluated three different encoding models that instantiate each of the three hypotheses listed above. We used linear regression to fit each encoding model to the fMRI data recorded from each voxel, and we evaluated each fit model by estimating the amount of variance it predicted in a withheld portion of the data set. We found that voxel-wise models based on Fourier power or the subjective distance to objects in each scene predicted much of the variance predicted by a model based on object categories. Furthermore, the response variance explained by these three models is largely shared, and the individual models explain little unique variance in responses. Based on an evaluation of previous studies and the data we present here, we conclude that there is currently no good basis to favor any one of the three alternative hypotheses about visual representation in scene-selective areas. We offer suggestions for further studies that may help resolve this issue.

  17. GSHR, a Web-Based Platform Provides Gene Set-Level Analyses of Hormone Responses in Arabidopsis

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    Xiaojuan Ran

    2018-01-01

    Full Text Available Phytohormones regulate diverse aspects of plant growth and environmental responses. Recent high-throughput technologies have promoted a more comprehensive profiling of genes regulated by different hormones. However, these omics data generally result in large gene lists that make it challenging to interpret the data and extract insights into biological significance. With the rapid accumulation of theses large-scale experiments, especially the transcriptomic data available in public databases, a means of using this information to explore the transcriptional networks is needed. Different platforms have different architectures and designs, and even similar studies using the same platform may obtain data with large variances because of the highly dynamic and flexible effects of plant hormones; this makes it difficult to make comparisons across different studies and platforms. Here, we present a web server providing gene set-level analyses of Arabidopsis thaliana hormone responses. GSHR collected 333 RNA-seq and 1,205 microarray datasets from the Gene Expression Omnibus, characterizing transcriptomic changes in Arabidopsis in response to phytohormones including abscisic acid, auxin, brassinosteroids, cytokinins, ethylene, gibberellins, jasmonic acid, salicylic acid, and strigolactones. These data were further processed and organized into 1,368 gene sets regulated by different hormones or hormone-related factors. By comparing input gene lists to these gene sets, GSHR helped to identify gene sets from the input gene list regulated by different phytohormones or related factors. Together, GSHR links prior information regarding transcriptomic changes induced by hormones and related factors to newly generated data and facilities cross-study and cross-platform comparisons; this helps facilitate the mining of biologically significant information from large-scale datasets. The GSHR is freely available at http://bioinfo.sibs.ac.cn/GSHR/.

  18. GSHR, a Web-Based Platform Provides Gene Set-Level Analyses of Hormone Responses in Arabidopsis.

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    Ran, Xiaojuan; Liu, Jian; Qi, Meifang; Wang, Yuejun; Cheng, Jingfei; Zhang, Yijing

    2018-01-01

    Phytohormones regulate diverse aspects of plant growth and environmental responses. Recent high-throughput technologies have promoted a more comprehensive profiling of genes regulated by different hormones. However, these omics data generally result in large gene lists that make it challenging to interpret the data and extract insights into biological significance. With the rapid accumulation of theses large-scale experiments, especially the transcriptomic data available in public databases, a means of using this information to explore the transcriptional networks is needed. Different platforms have different architectures and designs, and even similar studies using the same platform may obtain data with large variances because of the highly dynamic and flexible effects of plant hormones; this makes it difficult to make comparisons across different studies and platforms. Here, we present a web server providing gene set-level analyses of Arabidopsis thaliana hormone responses. GSHR collected 333 RNA-seq and 1,205 microarray datasets from the Gene Expression Omnibus, characterizing transcriptomic changes in Arabidopsis in response to phytohormones including abscisic acid, auxin, brassinosteroids, cytokinins, ethylene, gibberellins, jasmonic acid, salicylic acid, and strigolactones. These data were further processed and organized into 1,368 gene sets regulated by different hormones or hormone-related factors. By comparing input gene lists to these gene sets, GSHR helped to identify gene sets from the input gene list regulated by different phytohormones or related factors. Together, GSHR links prior information regarding transcriptomic changes induced by hormones and related factors to newly generated data and facilities cross-study and cross-platform comparisons; this helps facilitate the mining of biologically significant information from large-scale datasets. The GSHR is freely available at http://bioinfo.sibs.ac.cn/GSHR/.

  19. Fourier power, subjective distance, and object categories all provide plausible models of BOLD responses in scene-selective visual areas

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    Lescroart, Mark D.; Stansbury, Dustin E.; Gallant, Jack L.

    2015-01-01

    Perception of natural visual scenes activates several functional areas in the human brain, including the Parahippocampal Place Area (PPA), Retrosplenial Complex (RSC), and the Occipital Place Area (OPA). It is currently unclear what specific scene-related features are represented in these areas. Previous studies have suggested that PPA, RSC, and/or OPA might represent at least three qualitatively different classes of features: (1) 2D features related to Fourier power; (2) 3D spatial features such as the distance to objects in a scene; or (3) abstract features such as the categories of objects in a scene. To determine which of these hypotheses best describes the visual representation in scene-selective areas, we applied voxel-wise modeling (VM) to BOLD fMRI responses elicited by a set of 1386 images of natural scenes. VM provides an efficient method for testing competing hypotheses by comparing predictions of brain activity based on encoding models that instantiate each hypothesis. Here we evaluated three different encoding models that instantiate each of the three hypotheses listed above. We used linear regression to fit each encoding model to the fMRI data recorded from each voxel, and we evaluated each fit model by estimating the amount of variance it predicted in a withheld portion of the data set. We found that voxel-wise models based on Fourier power or the subjective distance to objects in each scene predicted much of the variance predicted by a model based on object categories. Furthermore, the response variance explained by these three models is largely shared, and the individual models explain little unique variance in responses. Based on an evaluation of previous studies and the data we present here, we conclude that there is currently no good basis to favor any one of the three alternative hypotheses about visual representation in scene-selective areas. We offer suggestions for further studies that may help resolve this issue. PMID:26594164

  20. The structure of arabidopsis thaliana OST1 provides insights into the kinase regulation mechanism in response to osmotic stress

    KAUST Repository

    Yunta, Cristina

    2011-11-01

    SnRK [SNF1 (sucrose non-fermenting-1)-related protein kinase] 2.6 [open stomata 1 (OST1)] is well characterized at molecular and physiological levels to control stomata closure in response to water-deficit stress. OST1 is a member of a family of 10 protein kinases from Arabidopsis thaliana (SnRK2) that integrates abscisic acid (ABA)-dependent and ABA-independent signals to coordinate the cell response to osmotic stress. A subgroup of protein phosphatases type 2C binds OST1 and keeps the kinase dephosphorylated and inactive. Activation of OST1 relies on the ABA-dependent inhibition of the protein phosphatases type 2C and the subsequent self-phosphorylation of the kinase. The OST1 ABA-independent activation depends on a short sequence motif that is conserved among all the members of the SnRK2 family. However, little is known about the molecular mechanism underlying this regulation. The crystallographic structure of OST1 shows that ABA-independent regulation motif stabilizes the conformation of the kinase catalytically essential α C helix, and it provides the basis of the ABA-independent regulation mechanism for the SnRK2 family of protein kinases. © 2011 Elsevier Ltd. All rights reserved.

  1. Transcriptome analysis provides insights into hepatic responses to moderate heat stress in the rainbow trout (Oncorhynchus mykiss).

    Science.gov (United States)

    Li, Yongjuan; Huang, Jinqiang; Liu, Zhe; Zhou, Yanjing; Xia, Binpeng; Wang, Yongjie; Kang, Yujun; Wang, Jianfu

    2017-07-01

    The rainbow trout is an economically important fish in the world. The limited stress tolerance of this species to high summer-like temperatures usually leads to mass mortality and great economic loss. However, there is limited information on the mechanisms underlying moderate heat responses in the liver of the rainbow trout. Here, we performed transcriptome profiling of rainbow trout liver under moderate heat stress by using the Hiseq™ 4000 sequencing platform. More than 277 million clean reads were obtained from 6 libraries and aligned against the rainbow trout genome. A total of 128 unique transcripts were differentially expressed in the liver under heat-stress and control conditions, many heat shock protein genes for thermoregulation and some novel genes involved in heat stress were identified. Nine of the differently expressed genes were further validated by qRT-PCR. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that several pathways, including those for protein metabolism, energy metabolism, and immune system, were influenced by heat stress. Moreover, an important protein-processing pathway in the endoplasmic reticulum (ER) was identified, and the key role of ER-associated degradation and function of calpain as an upstream regulator of apoptosis were confirmed under heat stress. The results of this study provide a comprehensive overview of heat stress-induced transcriptional patterns in rainbow trout liver and would be particularly useful for further studies on the molecular mechanisms underlying responses to heat stress in this species. Copyright © 2017. Published by Elsevier B.V.

  2. Phloem sap proteome studied by iTRAQ provides integrated insight into salinity response mechanisms in cucumber plants.

    Science.gov (United States)

    Fan, Huaifu; Xu, Yanli; Du, Changxia; Wu, Xue

    2015-07-01

    Cucumber is an economically important crop as well as a model system for plant vascular biology. Salinity is one of the major environmental factors limiting plant growth. Here, we used an iTRAQ-based quantitative proteomics approach for comparative analysis of protein abundances in cucumber phloem sap in response to salt. A total of 745 distinct proteins were identified and 111 proteins were differentially expressed upon salinity in sensitive and tolerant cultivars, of which 69 and 65 proteins changed significantly in sensitive and tolerant cultivars, respectively. A bioinformatics analysis indicated that cucumber phloem employed a combination of induced metabolism, protein turnover, common stress response, energy and transport, signal transduction and regulation of transcription, and development proteins as protection mechanisms against salinity. The proteins that were mapped to the carbon fixation pathway decreased in abundance in sensitive cultivars and had no change in tolerant cultivars under salt stress, suggesting that this pathway may promote salt tolerance by stabilizing carbon fixation and maintaining the essential energy and carbohydrates in tolerant cultivars. This study leads to a better understanding of the salinity mechanism in cucumber phloem and provides a list of potential gene targets for the further engineering of salt tolerance in plants. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Enhanced expression of indoleamine 2,3-dioxygenase in Helicobacter pylori-infected human gastric mucosa modulates Th1/Th2 pathway and interleukin 17 production.

    Science.gov (United States)

    Larussa, Tiziana; Leone, Isabella; Suraci, Evelina; Nazionale, Immacolata; Procopio, Teresa; Conforti, Francesco; Abenavoli, Ludovico; Hribal, Marta L; Imeneo, Maria; Luzza, Francesco

    2015-02-01

    Indoleamine 2,3 dioxygenase (IDO) interferes with immune responses. Host immune response against Helicobacter pylori is involved in the persistence of the infection and its related diseases. To investigate the role of IDO in the regulation of Th1/Th2 and Th17 pathways in H. pylori infection. Gastric biopsy samples were taken from 42 patients who underwent endoscopy and evaluated for the expression of IDO by Western blotting. Gastritis was assessed by the Sydney system score. In a subgroup of patients, biopsies were treated with the IDO inhibitor 1-methyl-L-tryptophan and the expression of interferon-γ (IFN-γ) mRNA and that of T-bet, interleukin-17 (IL-17), and IL-4 determined by real-time PCR and Western blotting, respectively. IDO expression was found to be enhanced (p = .001) in gastric biopsies from H. pylori-infected (n = 18) compared with uninfected (n = 24) patients. Levels of IDO expression were inversely related to the gastritis score (r = -.684, p = .002) in H. pylori-infected gastric mucosa, but not in uninfected mucosa. In gastric biopsy cultures, IDO inhibition increased the expression of IFN-γ mRNA (p = .014), T-bet (p = .045), and IL-17 (p = .02) while decreasing that of IL-4 (p = .048). In H. pylori-infected human gastric mucosa, an enhanced expression of IDO is capable of modulating Th1/Th2 and Th17 pathways. This mechanism lowers gastric inflammation, possibly contributing to the persistence of H. pylori. Targeting the IDO pathway may be a new strategy for modulating H. pylori-induced mucosal immune response. © 2014 John Wiley & Sons Ltd.

  4. The responsibility of gynecologists and obstetricians in providing safe abortion services within the limits of the law.

    Science.gov (United States)

    Faúndes, Anibal

    2017-10-01

    Approximately 47 000 women die each year worldwide as a result of the complications of unsafe abortion, almost exclusively in low- and middle-income countries with restrictive abortion laws. In these countries, very few women who comply with the conditions imposed by the law can access safe abortion services in the public health system. The main obstacle is the unwillingness of gynecologists and obstetricians to provide abortion services by claiming conscientious objection, which is often used to hide their fear of the stigma associated with abortion. This happens because many colleagues are unaware that without access to legal services these women will resort to an unsafe abortion and its consequences. This violates the statement from FIGO's Committee for the Ethical Aspects of Human Reproduction and Women's Health, which asserts that: "The primary conscientious duty of obstetrician-gynecologists is at all times to treat, or provide benefit and prevent harm, to the patients for whose care they are responsible. Any conscientious objection to treating a patient is secondary to this primary duty." © 2017 International Federation of Gynecology and Obstetrics.

  5. DNA Immunization Against Amyloid beta 42 has High Potential as Safe Therapy for Alzheimer’s Disease as it Diminishes Antigen-Specific Th1 and Th17 Cell Proliferation

    Science.gov (United States)

    Lambracht-Washington, Doris; Qu, Bao-Xi; Fu, Min; Anderson, Larry D.; Stüve, Olaf; Eagar, Todd N.

    2012-01-01

    The pathogenesis of Alzheimer’s disease (AD) has been strongly associated with the accumulation of amyloid beta (Aβ) peptides in brain, and immunotherapy targeting Aβ provides potential for AD prevention. A clinical trial in which AD patients were immunized with Aβ42 peptide was stopped when 6% of participants showed meningoencephalitis, apparently due to an inflammatory Th1 immune response. Previously, we and other have shown that Aβ42 DNA vaccination via gene gun generates a Th2 cellular immune response, which was shown by analyses of the respective antibody isotype profiles. We also determined that in vitro T cell proliferation in response to Aβ42 peptide re-stimulation was absent in DNA Aβ42 trimer-immunized mice when compared to Aβ42 peptide-immunized mice. To further characterize this observation prospectively and longitudinally, we analyzed the immune response in wild-type mice after vaccination with Aβ42 trimer DNA and Aβ42 peptide with Quil A adjuvant. Wild-type mice were immunized with short-term (1–3× vaccinations) or long-term (6× vacinations) immunization strategies. Antibody titers and isotype profiles of the Aβ42 specific antibodies, as well as cytokine profiles and cell proliferation studies from this longitudinal study were determined. Sufficient antibody titers to effectively reduce Aβ42, but an absent T cell proliferative response and no IFNγ or IL-17 secretion after Aβ42 DNA trimer immunization minimizes the risk of inflammatory activities of the immune system towards the self antigen Aβ42 in brain. Therefore, Aβ42 DNA trimer immunization has a high probability to be effective and safe to treat patients with early AD. PMID:21625960

  6. Respiratory syncytial virus (RSV) evades the human adaptive immune system by skewing the Th1/Th2 cytokine balance toward increased levels of Th2 cytokines and IgE, markers of allergy--a review.

    Science.gov (United States)

    Becker, Yechiel

    2006-10-01

    discussed. The aim of the present review is to base RSV pathogenicity on the numerous very good analyses of the virus genes and to suggest a therapeutic approach to treatment that is directed at preventing the inhibitory effects of Th2 cytokines on the adaptive immune system of the patients, instead of inhibiting RSV replication by antivirals. The review of the molecular research on the role of the viral fusion (F) and attachment (G) glycoproteins of RSV provided information on their role in the virus infection: early in infection the F glycoprotein induces Th1 cells to release the Th1 cytokines IL-2, IL-12 and IFN-gamma to activate precursors CTLs (pCTLs) to become anti-RSV CTLs. The G and sG glycoproteins attach to FKNR1(+) ciliary respiratory epithelial cells as well as directly to eosinophils to the lungs. The sG T cell antigen can also induce the release of large amounts of Th2 cytokines from CD4(+) T cells and from FCepsilonRI(+) mast cells, basophils and monocytes. By comparison to HIV-1 gp120 it is possible to show that in the G and sG proteins the T cell antigen resembles the CD4(+) T cell superantigen (=allergen) domain of HIV-1 gp120 which aggregates with IgE/FCepsilonRI(+) hematopoietic cells. The increased IL-4 level in the serum inhibits the adaptive immune response: IL-4Ralpha(+) Th1 cells stop Th1 cytokine synthesis and IL-4Ralpha(+) B cells stop the synthesis of antiviral IgG and IgA and switch to IgE synthesis. In addition, the hematopoietic cells release histamine and prostaglandin which induce wheezing. The gradual increase of sG molecules creates a gradient of fractalkine (FKN) which directs IL-5-activated eosinophils to the lungs of the patient.

  7. TLR2 and TLR4 co-activation utilizes distinct signaling pathways for the production of Th1/Th2/Th17 cytokines in neonatal immune cells.

    Science.gov (United States)

    Sugitharini, V; Shahana, P; Prema, A; Berla Thangam, E

    2016-09-01

    Co-activation of TLR2 and TLR4 by gram negative and gram positive bacterial ligands induces a robust pro-inflammatory response in inflammatory cells. In order to understand the signaling mechanism, we aimed to delineate the signaling molecules involved in TLR2 and TLR4 co-activation in neonatal immune cells for the production of Th1/Th2/Th17 inflammatory cytokines. For this, we pretreated cord blood and peripheral blood mononuclear and human mast cells with specific signaling molecule inhibitors such as BAY117082, PD98059 and LY294002 and then stimulated with LPS and PGN and assayed for cytokines IL-6, IL-12/IL-23p40 (Th1), IL-13 (Th2), IL-23 (Th17) and RANTES secretion. We found that upon co-stimulation the phosphorylation of NFκBp65, ERK1/2 and Akt was found to be higher than when stimulated with individual ligands in CBMCs. Also, when compared to adult cells, neonatal cells were more potent in the activation of ERK and Akt through TLR2 and TLR4 co-activation. In addition, neonatal cells possess similar capacity to activate NFκB as that of adult cells for IL-6 secretion. Furthermore, all three signaling molecules were found to be involved in the production of Th17 cytokines which is detrimental during inflammation induced by infection in neonates whereas NFκB is mainly involved in the induction of pro-inflammatory response and Th2 cytokines production. In conclusion, different signaling molecules were utilized for the production of different cytokines in immune cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Dendritic cell-secreted lipocalin2 induces CD8+ T-cell apoptosis, contributes to T-cell priming and leads to a TH1 phenotype.

    Directory of Open Access Journals (Sweden)

    Melanie Floderer

    Full Text Available Lipocalin 2 (LCN2, which is highly expressed by dendritic cells (DCs when treated with dexamethasone (Dex and lipopolysaccharide (LPS, plays a key role in the defence against bacteria and is also involved in the autocrine apoptosis of T-cells. However, the function of LCN2 when secreted by DCs is unknown: this is a critical gap in our understanding of the regulation of innate and adaptive immune systems. Tolerance, stimulation and suppression are functions of DCs that facilitate the fine-tuning of the immune responses and which are possibly influenced by LCN2 secretion. We therefore examined the role of LCN2 in DC/T-cell interaction. WT or Lcn2-/- bone marrow-derived DCs were stimulated with LPS or LPS+IFN-γ with and without Dex and subsequently co-cultured with T-cells from ovalbumin-specific TCR transgenic (OT-I and OT-II mice. We found that CD8+ T-cell apoptosis was highly reduced when Lcn2-/- DCs were compared with WT. An in vivo CTL assay, using LPS-treated DCs, showed diminished killing ability in mice that had received Lcn2-/- DCs compared with WT DCs. As a consequence, we analysed T-cell proliferation and found that LCN2 participates in T-cell-priming in a dose-dependent manner and promotes a TH1 microenvironment. DC-secreted LCN2, whose function has previously been unknown, may in fact have an important role in regulating the balance between TH1 and TH2. Our results yield insights into DC-secreted LCN2 activity, which could play a pivotal role in cellular immune therapy and in regulating immune responses.

  9. Regulation of nasal airway homeostasis and inflammation in mice by SHP-1 and Th2/Th1 signaling pathways.

    Directory of Open Access Journals (Sweden)

    Seok Hyun Cho

    Full Text Available Allergic rhinitis is a chronic inflammatory disease orchestrated by Th2 lymphocytes. Src homology 2 domain-containing protein tyrosine phosphatase (SHP-1 is known to be a negative regulator in the IL-4α/STAT-6 signaling pathway of the lung. However, the role of SHP-1 enzyme and its functional relationship with Th2 and Th1 cytokines are not known in the nasal airway. In this study, we aimed to study the nasal inflammation as a result of SHP-1 deficiency in viable motheaten (mev mice and to investigate the molecular mechanisms involved. Cytology, histology, and expression of cytokines and chemokines were analyzed to define the nature of the nasal inflammation. Targeted gene depletion of Th1 (IFN-γ and Th2 (IL-4 and IL-13 cytokines was used to identify the critical pathways involved. Matrix metalloproteinases (MMPs were studied to demonstrate the clearance mechanism of recruited inflammatory cells into the nasal airway. We showed here that mev mice had a spontaneous allergic rhinitis-like inflammation with eosinophilia, mucus metaplasia, up-regulation of Th2 cytokines (IL-4 and IL-13, chemokines (eotaxin, and MMPs. All of these inflammatory mediators were clearly counter-regulated by Th2 and Th1 cytokines. Deletion of IFN-γ gene induced a strong Th2-skewed inflammation with transepithelial migration of the inflammatory cells. These findings suggest that SHP-1 enzyme and Th2/Th1 paradigm may play a critical role in the maintenance of nasal immune homeostasis and in the regulation of allergic rhinitis.

  10. Correlation of body mass index with Th1/Th2 balance, adhesion molecules and insulin signal transduction in infertile patients

    Directory of Open Access Journals (Sweden)

    Hui-Juan Zhang

    2017-11-01

    Full Text Available Objective: To study the correlation of body mass index with Th1/Th2 balance, adhesion molecules and insulin signal transduction in infertile patients. Methods: A total of 132 patients who received diagnostic curettage due to infertility in Tangshan Maternal and Child Health Hospital between June 2015 and March 2016 were selected as the research subjects and divided into the normal group with BMI 30 kg/m 2 according to BMI, and the levels of Th1/ Th2 cytokines in serum as well as the expression of Th1/Th2 transcription factors, adhesion molecules and insulin signal pathway molecules in endometrial tissue were detected. Results: IFN-γ and TNF-α levels in serum of obesity group and overweight group were significantly higher than those of control group while IL-4, IL-5 and IL-13 levels in serum as well as CD44V6, N-cadherin, FAK, ICAM-1, GLUT-4, IRS-1, PI3K and AKT mRNA expression in endometrial tissue were significantly lower than those of control group; IFN-γ and TNF-α levels in serum of obesity group were significantly higher than those of overweight group while IL-4, IL-5 and IL-13 levels in serum as well as CD44V6, N-cadherin, FAK, ICAM-1, GLUT-4, IRS-1, PI3K and AKT mRNA expression in endometrial tissue were significantly lower than those of overweight group. Conclusion: Weight gain can aggravate the Th1/Th2 disorder, reduce the adhesion molecule expression and hinder the insulin signal transduction in infertile patients.

  11. Comparative Proteomic Analysis of the Graft Unions in Hickory (Carya cathayensis Provides Insights into Response Mechanisms to Grafting Process

    Directory of Open Access Journals (Sweden)

    Daoliang Yan

    2017-04-01

    Full Text Available Hickory (Carya cathayensis, a tree with high nutritional and economic value, is widely cultivated in China. Grafting greatly reduces the juvenile phase length and makes the large scale cultivation of hickory possible. To reveal the response mechanisms of this species to grafting, we employed a proteomics-based approach to identify differentially expressed proteins in the graft unions during the grafting process. Our study identified 3723 proteins, of which 2518 were quantified. A total of 710 differentially expressed proteins (DEPs were quantified and these were involved in various molecular functional and biological processes. Among these DEPs, 341 were up-regulated and 369 were down-regulated at 7 days after grafting compared with the control. Four auxin-related proteins were down-regulated, which was in agreement with the transcription levels of their encoding genes. The Kyoto Encyclopedia of Genes and Genomes (KEGG analysis showed that the ‘Flavonoid biosynthesis’ pathway and ‘starch and sucrose metabolism’ were both significantly up-regulated. Interestingly, five flavonoid biosynthesis-related proteins, a flavanone 3-hyfroxylase, a cinnamate 4-hydroxylase, a dihydroflavonol-4-reductase, a chalcone synthase, and a chalcone isomerase, were significantly up-regulated. Further experiments verified a significant increase in the total flavonoid contents in scions, which suggests that graft union formation may activate flavonoid biosynthesis to increase the content of a series of downstream secondary metabolites. This comprehensive analysis provides fundamental information on the candidate proteins and secondary metabolism pathways involved in the grafting process for hickory.

  12. CD36 Provides Host Protection Against Klebsiella pneumoniae Intrapulmonary Infection by Enhancing Lipopolysaccharide Responsiveness and Macrophage Phagocytosis.

    Science.gov (United States)

    Olonisakin, Tolani F; Li, Huihua; Xiong, Zeyu; Kochman, Elizabeth J K; Yu, Minting; Qu, Yanyan; Hulver, Mei; Kolls, Jay K; St Croix, Claudette; Doi, Yohei; Nguyen, Minh-Hong; Shanks, Robert M Q; Mallampalli, Rama K; Kagan, Valerian E; Ray, Anuradha; Silverstein, Roy L; Ray, Prabir; Lee, Janet S

    2016-12-15

    Klebsiella pneumoniae remains an important cause of intrapulmonary infection and invasive disease worldwide. K. pneumoniae can evade serum killing and phagocytosis primarily through the expression of a polysaccharide capsule, but its pathogenicity is also influenced by host factors. We examined whether CD36, a scavenger receptor that recognizes pathogen and modified self ligands, is a host determinant of K. pneumoniae pathogenicity. Despite differences in serum sensitivity and virulence of 3 distinct K. pneumoniae (hypermucoviscous K1, research K2, and carbapenemase-producing ST258) strains, the absence of CD36 significantly increased host susceptibility to acute intrapulmonary infection by K. pneumoniae, regardless of strain. We demonstrate that CD36 enhances LPS responsiveness to K. pneumoniae to increase downstream cytokine production and macrophage phagocytosis that is independent of polysaccharide capsular antigen. Our study provides new insights into host determinants of K. pneumoniae pathogenicity and raises the possibility that functional mutations in CD36 may predispose individuals to K. pneumoniae syndromes. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  13. Serum levels of Th1/Th2 cytokines in aged patients and their correlation with eczema development and clinical manifestation

    Directory of Open Access Journals (Sweden)

    Wei-Gang Wang

    2016-05-01

    Full Text Available Objective: To investigate variations of Th1/Th2 cytokine levels, as well as their correlation with eczema development and clinical manifestation in aged patients. Methods: A total of 92 patients (above 60 years old with eczema diagnosed by the outpatient department of dermatology and venerology of our hospital were included as the eczema group, while 60 aged patients without eczema as the healthy group. Patients' serum levels of Th1/Th2 cytokines were examined for inter-group comparison and stratified analysis as per clinical manifestation. Results: Serum levels of interleukin (IL-2, IL-4, IL-10, IL-12, tumor necrosis factor (TNF- α and interferon (IFN- γ were all significantly higher in patients of the eczema group than the healthy group. Acute stage levels of IL-2, IL-4, IL-10 and IFN-γ were significantly higher in patients of the eczema group than the healthy group. There was no significant difference in the levels of IL-12 and TNF-α between patients of the acute stage and those of the chronic stage. And no significant difference existed in the levels of IL-2, IL-4, IL-10, IL-12, TNF-α and IFN-γ between generalized and localized eczema patients. Conclusion: Compared with the healthy population, Th1/Th2 cytokine levels are significantly different in eczema patients, especially those in the acute stage.

  14. Effects of Pristane Alone or Combined with Chloroquine on Macrophage Activation, Oxidative Stress, and Th1/Th2 Skewness

    Directory of Open Access Journals (Sweden)

    Qiufang Ouyang

    2014-01-01

    Full Text Available We investigated the protective role of chloroquine against pristane-induced macrophage activation, oxidative stress, and Th1/Th2 skewness in C57BL/6J mice. Those mice were treated with pristane alone or combined with chloroquine. Hematological and biochemical parameters, macrophage phagocytic function, the oxidant/antioxidant index, cytokine for IFN-γ, TNF-α, IL-4, and IL-6, and the isotypes of IgG2a and IgG1 were determined. And the expression of T-bet/GATA-3 and IL-12/IL-10 mRNA in spleen were analyzed by real-time PCR. We found that pristane treatment for a period of 12 or 24 weeks triggered macrophage activation syndrome, characterized by hemophagocytosis in spleen and peripheral blood, enhanced lipid phagocytosis by peritoneal macrophages in vitro, erythropenia and leucopenia, increased anti-Smith, lactic dehydrogenase, triglyceride, and ferritin, as well as hypercytokinemia of IFN-γ, TNF-α, IL-4, and IL-6. In parallel, a significant increase in lipid peroxidation and a decrease in superoxide dismutase, glutathione, and catalase activity, as well as a skewed Th1/Th2 balance in spleen, were observed. However, chloroquine supplementation showed a remarkable amelioration of these abnormalities. Our data indicate that pristane administration induces macrophage activation, oxidative stress, and Th1/Th2 skewness, which can be attenuated by chloroquine.

  15. The Role of Th1/Th2 Cytokine Balance in Gulf War-Related Illness

    Science.gov (United States)

    2001-02-01

    Ramirez et al, 1996). Finally, although natural infection with Bordetella pertussis and its whole cell-derived vaccine promote a strong Thl response...the stress of deployment with additional effects of the T helper 2 (Th2) adjuvant pertussis could skew the immune response towards a Th2 profile. The...paradoxically the acellular vaccine component pertussis toxin used as adjuvant in GW vaccinations causes Th2 deviation (Munoz et al, 1990; Mu et al, 1993

  16. Modern diets and diseases: NO-zinc balance. Under Th1, zinc and nitrogen monoxide (NO) collectively protect against viruses, AIDS, autoimmunity, diabetes, allergies, asthma, infectious diseases, atherosclerosis and cancer.

    Science.gov (United States)

    Sprietsma, J E

    1999-07-01

    Thanks to progress in zinc research, it is now possible to describe in more detail how zinc ions (Zn++) and nitrogen monoxide (NO), together with glutathione (GSH) and its oxidized form, GSSG, help to regulate immune responses to antigens. NO appears to be able to liberate Zn++ from metallothionein (MT), an intracellular storage molecule for metal ions such as zinc (Zn++) and copper (Cu++). Both Zn++ and Cu++ show a concentration-dependent inactivation of a protease essential for the proliferation of the AIDS virus HIV-1, while zinc can help prevent diabetes complications through its intracellular activation of the enzyme sorbitol dehydrogenase (SDH). A Zn++ deficiency can lead to a premature transition from efficient Th1-dependent cellular antiviral immune functions to Th2-dependent humoral immune functions. Deficiencies of Zn++, NO and/or GSH shift the Th1/Th2 balance towards Th2, as do deficiencies of any of the essential nutrients (ENs) - a group that includes methionine, cysteine, arginine, vitamins A, B, C and E, zinc and selenium (Se) - because these are necessary for the synthesis and maintenance of sufficient amounts of GSH, MT and NO. Via the Th1/Th2 balance, Zn++, NO, MT and GSH collectively determine the progress and outcome of many diseases. Disregulation of the Th1/Th2 balance is responsible for autoimmune disorders such as diabetes mellitus. Under Th2, levels of interleukin-4 (II-4), II-6, II-10, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) are raised, while levels of II-2, Zn++, NO and other substances are lowered. This makes things easier for viruses like HIV-1 which multiply in Th2 cells but rarely, if ever, in Th1 cells. AIDS viruses (HIVs) enter immune cells with the aid of the CD4 cell surface receptor in combination with a number of co-receptors which include CCR3, CCR5 and CXCR4. Remarkably, the cell surface receptor for LTB4 (BLTR) also seems to act as a co-receptor for CD4, which helps HIVs to infect immune cells. The Th2 cytokine II-4

  17. Quantificação das citocinas séricas Th1/Th2 por citometria de fluxo no linfoma de Hodgkin clássico Measurement of Th1/Th2 serum cytokines by flow cytometry in classical Hodgkin lymphoma

    Directory of Open Access Journals (Sweden)

    Adriana K. Mitelman

    2009-08-01

    Full Text Available O linfoma de Hodgkin clássico (LHC é uma neoplasia com distúrbio na produção de citocinas. Estudos demonstram que o padrão anormal das citocinas no linfonodo acometido pela lesão contribui não somente com a proliferação das células malignas H-RS, como também com o característico infiltrado hiper-reativo que compõe o tecido no LHC. Esta disfunção pode ser observada tanto no quadro clínico dos pacientes, como nas características histopatológicas: sintomas B, deficiência na resposta imune celular, bandas de colágeno e eosinofilia. As concentrações séricas das citocinas Th1 (IL-2, TNF, INF-γ e Th2 (IL-4, IL-5, IL-10 foram estudadas em 45 pacientes com LHC, ao diagnóstico, e em 34 doadores saudáveis, por citometria de fluxo (CBA - cytometric beads array. Houve aumento das concentrações das citocinas TNF (pClassical Hodgkin lymphoma (CHL is a malignancy with an abnormal or unbalanced secretion/production of cytokines, which might support the growth of H-RS cells, their surrounding reactive bystander cells and may be responsible for the typical clinical and histopathologic features of CHL: systemic B symptoms, an apparent defect in cell-mediated immune response, tumor fibrosis and eosinophilic infiltrate. Serum concentrations of IL-2, IL-4, IL5, IL-10, TNF and IFN-γ (Th1/Th2 were measured in 45 patients at diagnosis of classical Hodgkin lymphoma and in 34 healthy controls by cytometric beads array (CBA. Levels of TNF (p<0.01, INF-γ(p<0.01, IL-4 (p=0.01, IL-5 (p<0.01 e IL-10 (p<0.01 were significantly higher in patients compared to the control group. No difference was observed for IL-2 between the two groups. On correlating Th1/Th2 cytokine concentrations with clinical risk factors, elevated IL-10 (Th2 levels are associated with variables that suggest worse prognoses including III/IV stage (p=0.01, B-symptoms (p=0.04, hemoglobin < 10.5g/dL (p=0.01, lymphocytes < 600/mm³ (p=0.01 and according to the seven

  18. Using Audience Response Technology to provide formative feedback on pharmacology performance for non-medical prescribing students - a preliminary evaluation

    Directory of Open Access Journals (Sweden)

    Mostyn Alison

    2012-11-01

    individualised handsets and personalised formative feedback highly. The significant correlation between ART response scores and student exam scores suggests that formative feedback can provide students with a useful reference point in terms of their level of exam-readiness.

  19. Improved outcome of chronic Pseudomonas aeruginosa lung infection is associated with induction of a Th1-dominated cytokine response

    DEFF Research Database (Denmark)

    Moser, C; Jensen, P O; Kobayashi, O

    2002-01-01

    Repeated challenge with antigen is involved in the pathogenesis of a variety of pulmonary diseases. Patients with cystic fibrosis (CF) experience recurrent pulmonary colonization with Pseudomonas aeruginosa before establishment of chronic lung infection. To mimic recurrent lung infections in CF...... patients, the lungs of susceptible BALB/c mice were re-infected with P. aeruginosa 14 days after the initial infection. Singly-infected BALB/c mice, as well as non-infected mice, were used as controls. Decreased mortality and milder lung inflammation in re-infected BALB/c mice, as well as a tendency...... production, in chronic P. aeruginosa lung infection in CF....

  20. Transcriptional modulation of pattern recognition receptors in chronic colitis in mice is accompanied with Th1 and Th17 response

    NARCIS (Netherlands)

    Zheng, Bin|info:eu-repo/dai/nl/313932166; Morgan, Mary E|info:eu-repo/dai/nl/273313215; van de Kant, Hendrik J G|info:eu-repo/dai/nl/304838799; Garssen, Johan|info:eu-repo/dai/nl/086369962; Folkerts, Gert|info:eu-repo/dai/nl/087131811; Kraneveld, Aletta D|info:eu-repo/dai/nl/126612838

    2017-01-01

    Pattern recognition receptors (PRRs) may contribute to inflammatory bowel diseases (IBD) development due to their microbial-sensing ability and the unique microenvironment in the inflamed gut. In this study, the PRR mRNA expression profile together with T cell-associated factors in the colon was

  1. A Leptospira borgpetersenii Serovar Hardjo vaccine induces a Th1 response, activates NK cells, and reduces renal colonization

    Science.gov (United States)

    Chronic infection of cattle with Leptospira borgpetersenii serovar Hardjo reduces animal production through reproductive failure and presents a persistent health threat to workers in the animal industry. Cattle are maintenance hosts for serovar Hardjo and development of a protective vaccine has bee...

  2. Monomethylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated Th1 lymphocyte responses

    DEFF Research Database (Denmark)

    Litjens, Nicolle H R; Rademaker, Mirjam; Ravensbergen, Bep

    2004-01-01

    Psoriasis vulgaris, a type-1 cytokine-mediated chronic skin disease, can be treated successfully with fumaric acid esters (FAE). Beneficial effects of this medication coincided with decreased production of IFN-gamma. Since dendritic cells (DC) regulate the differentiation of T helper (Th) cells, ...

  3. Improved outcome of chronic Pseudomonas aeruginosa lung infection is associated with induction of a Th1-dominated cytokine response

    DEFF Research Database (Denmark)

    Moser, C; Jensen, P O; Kobayashi, O

    2002-01-01

    Repeated challenge with antigen is involved in the pathogenesis of a variety of pulmonary diseases. Patients with cystic fibrosis (CF) experience recurrent pulmonary colonization with Pseudomonas aeruginosa before establishment of chronic lung infection. To mimic recurrent lung infections in CF...... for improved clearance of bacteria, was observed when compared with singly-infected mice. The improved outcome in re-infected mice correlated with changes in CD4 cell numbers. Surface expression of LFA-1 on pulmonary CD4 cells was increased in re-infected compared with singly-infected mice. Moreover...

  4. Evaluation of Th1 and Th17 cells cytokines in cell culture stimulated in women with recurrent spontaneous abortion

    Directory of Open Access Journals (Sweden)

    Y Varghaiyan

    2013-10-01

    Full Text Available Introduction: Various immunological abnormalities have been reported in women with RSA of unknown aetiologies including autoimmune abnormalities and increased cellular immunity such as elevated natural killer (NK , Th1 and Th17 cell levels. Th17 and Th1 cells play a central role during inflammation. Th1 cells product cytokines IFN-γ, IL-2 and Th17 cells mainly cytokines IL-17A, F, IL-22. The aim of this study is evaluation of Th1 and Th17 activity in women with recurrent spontaneous abortion. Methods: In this case-control study, 30 women with history of two or more abortion who at least 3 months past after last abortion considered as case group and 30 normal fertile healthy women with at least one delivery as control group. We determined the levels of IL-17A, F and IFN-γ in cell culture supernatant of peripheral blood mononuclear cells (PBMC stimulated with the mitogen phytohemagglutinin (PHA by enzyme-linked immunosorbent assay (ELISA method and compared in the two groups. The results obtained using the one-sample kolmogorov-smirnov Test, Kruskal-wallis Test and Spearman were analyzed using SPSS 16 software. Results: The level of IFN- γ in case group was significantly higher than control group (186/53±30/41 versus 88/06±21/44 pg/ml, P < 0.005. Also the level of IL-17 A, F in case group was significantly higher than control group (84/74±21/26 versus 28/41±8 pg/ml, P < 0.01. IFN-γ concentration showed positive correlation with IL-17 A, F in case group (P=0.015, r= 0.455. Conclusion: In this study the increased levels of cytokines IFN- γ and IL-17 A, F in women with recurrent spontaneous abortion shows a propensity of pro inflammation via Th17 and Th1 immunity and may be these cells play a pivotal role in rejecting fetus antigens.

  5. Propionibacterium acnes and the Th1/Th17 Axis, implications in acne pathogenesis and treatment

    Directory of Open Access Journals (Sweden)

    Kabir Sardana

    2017-01-01

    Full Text Available Acne vulgaris is one of the most commonly seen conditions and the immunological link is a topic of active research. Recently, the Th17 pathway has been found to play a pivotal role in acne. The adaptive immune response toward Propionibacterium acnes leads to activation of Th17 axis. Consequently, the Th17 cytokines (IL-17, IL-1 β, IL-6, and tumor growth factor, in turn, activate the various pathogenic steps in acne. Drugs such as Vitamin D3 and isotretinoin which target the Th17 pathway may offer an additional pathway for their therapeutic response.

  6. mTOR Inhibition Attenuates Dextran Sulfate Sodium-Induced Colitis by Suppressing T Cell Proliferation and Balancing TH1/TH17/Treg Profile.

    Directory of Open Access Journals (Sweden)

    Shurong Hu

    Full Text Available It has been established that mammalian target of Rapamycin (mTOR inhibitors have anti-inflammatory effects in models of experimental colitis. However, the underlying mechanism is largely unknown. In this research, we investigate the anti-inflammatory effects of AZD8055, a potent mTOR inhibitor, on T cell response in dextran sulfate sodium (DSS-induced colitis in mice, a commonly used animal model of inflammatory bowel diseases (IBD. Severity of colitis is evaluated by changing of body weight, bloody stool, fecal consistency, histology evaluation and cytokine expression. We find that AZD8055 treatment attenuates DSS-induced body weight loss, colon length shortening and pathological damage of the colon. And AZD8055 treatment decreases colonic expression of genes encoding the pro-inflammatory cytokines interferon-γ, interleukin (IL-17A, IL-1β,IL-6 and tumor necrosis factor(TNF-a and increases colonic expression of anti-inflammatory cytokines IL-10. We show that AZD8055 treatment decreases the percentages of CD4+ T cells and CD8+ T cells in spleen, lymph nodes and peripheral blood of mice. We also find that AZD8055 treatment significantly reduces the number of T helper 1(TH1 cells and TH17 cells and increases regulatory T (Treg cells in the lamina propria and mesenteric lymph nodes. Furthermore, we demonstrates that AZD8055 suppresses the proliferation of CD4+ and CD8+ T cells and the differentiation of TH1/TH17 cells and expands Treg cells in vitro. The results suggest that, in experimental colitis, AZD8055 exerts anti-inflammatory effect by regulating T helper cell polarization and proliferation.

  7. Batf3-dependent CD103+ dendritic cells are major producers of IL-12 that drive local Th1 immunity against Leishmania major infection in mice.

    Science.gov (United States)

    Martínez-López, María; Iborra, Salvador; Conde-Garrosa, Ruth; Sancho, David

    2015-01-01

    The role of different DC subsets in priming and maintenance of immunity against Leishmania major (L. major) infection is debated. The transcription factor basic leucine zipper transcription factor, ATF-like 3 (Batf3) is essential for the development of mouse CD103(+) DCs and some functions of CD8α(+) DCs. We found that CD103(+) DCs were significantly reduced in the dermis of Batf3-deficient C57BL/6 mice. Batf3(-/-) mice developed exacerbated and unresolved cutaneous pathology following a low dose of intradermal L. major infection in the ear pinnae. Parasite load was increased 1000-fold locally and expanded systemically. Batf3 deficiency did not affect L. major antigen presentation to T cells, which was directly exerted by CD8α(-) conventional DCs (cDCs) in the skin draining LN. However, CD4(+) T-cell differentiation in the LN and skin was skewed to nonprotective Treg- and Th2-cell subtypes. CD103(+) DCs are major IL-12 producers during L. major infection. Local Th1 immunity was severely hindered, correlating with impaired IL-12 production and reduction in CD103(+) DC numbers. Adoptive transfer of WT but not IL-12p40(-/-) Batf3-dependent DCs significantly improved anti-L. major response in infected Batf3(-/-) mice. Our results suggest that IL-12 production by Batf3-dependent CD103(+) DCs is crucial for maintenance of local Th1 immunity against L. major infection. © 2014 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Carbohydrate and glutamine supplementation modulates the Th1/Th2 balance after exercise performed at a simulated altitude of 4500 m.

    Science.gov (United States)

    Caris, Aline V; Lira, Fábio S; de Mello, Marco T; Oyama, Lila M; dos Santos, Ronaldo V T

    2014-01-01

    The aim of this study was to evaluate the effect of carbohydrate or glutamine supplementation, or a combination of the two, on the immune system and inflammatory parameters after exercise in simulated hypoxic conditions at 4500 m. Nine men underwent three sessions of exercise at 70% VO2peak until exhaustion as follows: 1) hypoxia with a placebo; 2) hypoxia with 8% maltodextrin (200 mL/20 min) during exercise and for 2 h after; and 3) hypoxia after 6 d of glutamine supplementation (20 g/d) and supplementation with 8% maltodextrin (200 mL/20 min) during exercise and for 2 h after. All procedures were randomized and double blind. Blood was collected at rest, immediately before exercise, after the completion of exercise, and 2 h after recovery. Glutamine, cortisol, cytokines, glucose, heat shock protein-70, and erythropoietin were measured in serum, and the cytokine production from lymphocytes was measured. Erythropoietin and interleukin (IL)-6 increased after exercise in the hypoxia group compared with baseline. IL-6 was higher in the hypoxia group than pre-exercise after exercise and after 2 h recovery. Cortisol did not change, whereas glucose was elevated post-exercise in the three groups compared with baseline and pre-exercise. Glutamine increased in the hypoxia + carbohydrate + glutamine group after exercise compared with baseline. Heat shock protein-70 increased post-exercise compared with baseline and pre-exercise and after recovery compared with pre-exercise, in the hypoxia + carbohydrate group. No difference was observed in IL-2 and IL-6 production from lymphocytes. IL-4 was reduced in the supplemented groups. Carbohydrate or glutamine supplementation shifts the T helper (Th)1/Th2 balance toward Th1 responses after exercise at a simulated altitude of 4500 m. The nutritional strategies increased in IL-6, suggesting an important anti-inflammatory effect. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Dynamics of adrenal steroids are related to variations in Th1 and Treg populations during Mycobacterium tuberculosis infection in HIV positive persons.

    Directory of Open Access Journals (Sweden)

    Maria Florencia Quiroga

    Full Text Available Tuberculosis (TB remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA, its circulating form DHEA-suphate (DHEA-s and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS, a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD, HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB, whereas dehydroepiandrosterone sulfate (DHEA-s levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS.

  10. Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection

    NARCIS (Netherlands)

    A.F. Brown (Aisling F.); A.G. Murphy (Alison G.); S.J. Lalor (Stephen J.); J.M. Leech (John M.); K.M. O’Keeffe (Kate M.); M. Mac Aogáin (Micheál); D.P. O’Halloran (Dara P.); K.A. Lacey (Keenan A.); M. Tavakol (Mehri); C.H. Hearnden (Claire H.); D. Fitzgerald-Hughes (Deirdre); H. Humphreys (Hilary); J.P. Fennell (Jérôme P.); W.J.B. van Wamel (Willem); T.J. Foster (Timothy J.); J.A. Geoghegan (Joan A.); E.C. Lavelle (Ed C.); T.R. Rogers (Thomas R.); R.M. McLoughlin (Rachel M.)

    2015-01-01

    textabstractMechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we

  11. Vaccination promotes TH1-like inflammation and survival in chronic Pseudomonas aeruginosa pneumonia in rats

    DEFF Research Database (Denmark)

    Johansen, H K; Hougen, H P; Cryz, S J

    1995-01-01

    In a rat model of chronic Pseudomonas aeruginosa lung infection mimicking cystic fibrosis (CF) we studied whether the inflammatory response could be altered by vaccination. Rats were immunized with either a depolymerized alginate toxin A conjugate (D-ALG toxin A), purified alginate, an O-polysacc......In a rat model of chronic Pseudomonas aeruginosa lung infection mimicking cystic fibrosis (CF) we studied whether the inflammatory response could be altered by vaccination. Rats were immunized with either a depolymerized alginate toxin A conjugate (D-ALG toxin A), purified alginate, an O......-polysaccharide toxin A conjugate, or sterile saline. After challenge none of the rats immunized with D-ALG toxin A died, in contrast to the other two vaccine groups combined (p = 0.03). A significant reduction in the severity of the macroscopic lung inflammation was seen in rats immunized with D-ALG toxin A, compared...... with the other three groups (p = 0.009). The histopathologic response in the control rats was dominated by numerous polymorphonuclear leukocytes (PMN) surrounding the alginate beads. In contrast, the histopathologic response in rats immunized with D-ALG toxin A changed within the first week after challenge from...

  12. The intravenous injection of oxidized LDL- or Apolipoprotein B100 – Coupled splenocytes promotes Th1 polarization in wildtype and Apolipoprotein E – Deficient mice

    Energy Technology Data Exchange (ETDEWEB)

    Steinmetz, Martin, E-mail: martin.steinmetz@ukb.uni-bonn.de [INSERM, Unit 970, Paris Cardiovascular Research Center, 75015 Paris (France); Internal Medicine II, University Hospital Bonn, 53105 Bonn (Germany); Ponnuswamy, Padmapriya; Laurans, Ludivine; Esposito, Bruno; Tedgui, Alain [INSERM, Unit 970, Paris Cardiovascular Research Center, 75015 Paris (France); Mallat, Ziad [INSERM, Unit 970, Paris Cardiovascular Research Center, 75015 Paris (France); Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke' s Hospital, Cambridge, CB2 2QQ (United Kingdom)

    2015-08-14

    Background: Th1 responses in atherosclerosis are mainly associated with the aggravation of atherosclerotic plaques, whereas Th2 responses lead to a less pronounced disease in mouse models. The fixation of antigens on cells by means of ethylene carbodiimide (ECDI), and subsequent injection of these antigen-coupled splenocytes (Ag-SP) to induce tolerance against the attached antigens, has been successfully used to treat murine type 1 diabetes or encephalomyelitis in. We analyzed this approach in a mouse model for atherosclerosis. Methods and results: OTII-transgenic mice that were treated with a single dose of 5 × 10{sup 7} OVA-coupled splenocytes (OVA-SP), had decreased splenocyte proliferation, and lower IFNγ production in vitro upon antigen recall. However, in vivo CD4 cell activation was increased. To try lipoprotein-derived, “atherosclerosis-associated” antigens, we first tested human oxidized LDL. In wild type mice, an increase of IFNγ production upon in vitro recall was detected in the oxLDL-SP group. In Apolipoprotein E − deficient (ApoE−/−) mice that received oxLDL-SP every 5 weeks for 20 weeks, we did not find any difference of atherosclerotic plaque burden, but again increased IFNγ production. To overcome xenogenous limitations, we then examined the effects of mouse Apolipoprotein B100 peptides P3 and P6. ApoB100-SP treatment again promoted a more IFNγ pronounced response upon in vitro recall. Flow cytometry analysis of cytokine secreting spleen cells revealed CD4 positive T cells to be mainly the source for IFNγ. In ApoE−/− mice that were administered ApoB100-SP during 20 weeks, the atherosclerotic plaque burden in aortic roots as well as total aorta was unchanged compared to PBS treated controls. Splenocyte proliferation upon antigen recall was not significantly altered in ApoB100-SP treated ApoE−/− mice. Conclusion: Although we did not observe a relevant anti-atherosclerotic benefit, the treatment with antigen

  13. Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling

    NARCIS (Netherlands)

    Smeets, Ruben L.; Fleuren, Wilco W. M.; He, Xuehui; Vink, Paul M.; Wijnands, Frank; Gorecka, Monika; Klop, Henri; Bauerschmidt, Sussane; Garritsen, Anja; Koenen, Hans J. P. M.; Joosten, Irma; Boots, Annemieke M. H.; Alkema, Wynand

    2012-01-01

    Background: T lymphocytes are orchestrators of adaptive immunity. Naive T cells may differentiate into Th1, Th2, Th17 or iTreg phenotypes, depending on environmental co-stimulatory signals. To identify genes and pathways involved in differentiation of Jurkat T cells towards Th1 and Th2 subtypes we

  14. Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling.

    NARCIS (Netherlands)

    Smeets, R.L.; Fleuren, W.W.M.; He, X.; Vink, P.M.; Wijnands, F.; Gorecka, M.; Klop, H.; Bauerschmidt, S.; Garritsen, A.; Koenen, H.J.P.M.; Joosten, I.; Boots, A.M.H.; Alkema, W.

    2012-01-01

    BACKGROUND: T lymphocytes are orchestrators of adaptive immunity. Naive T cells may differentiate into Th1, Th2, Th17 or iTreg phenotypes, depending on environmental co-stimulatory signals. To identify genes and pathways involved in differentiation of Jurkat T cells towards Th1 and Th2 subtypes we

  15. Simultaneous analysis of multiple T helper subsets in leprosy reveals distinct patterns of Th1, Th2, Th17 and Tregs markers expression in clinical forms and reactional events.

    Science.gov (United States)

    Azevedo, Michelle de Campos Soriani; Marques, Heloisa; Binelli, Larissa Sarri; Malange, Mariana Silva Vieira; Devides, Amanda Carreira; Silva, Eliane Aparecida; Fachin, Luciana Raquel Vincenzi; Ghidella, Cassio Cesar; Soares, Cleverson Teixeira; Garlet, Gustavo Pompermaier; Rosa, Patrícia Sammarco; Belone, Andrea de Farias Fernandes; Trombone, Ana Paula Favaro

    2017-12-01

    Leprosy is a chronic infectious disease caused by Mycobacterium leprae. Previous studies have demonstrated that the difference among clinical forms of leprosy can be associated with the immune response of patients, mainly by T helper (Th) and regulatory T cells (Tregs). Then, aiming at clarifying the immune response, the expression of cytokines related to Th1, Th2, Th17 and Tregs profiles were evaluated by qPCR in 87 skin biopsies from leprosy patients. Additionally, cytokines and anti-PGL-1 antibodies were determined in serum by ELISA. The results showed that the expression of various targets (mRNA) related to Th1, Th2, Th17 and Tregs were significantly modulated in leprosy when compared with healthy individuals, suggesting the presence of a mixed profile. In addition, the targets related to Th1 predominated in the tuberculoid pole and side and Th2 and Tregs predominated in the lepromatous pole and side; however, Th17 targets showed a mixed profile. Concerning reactional events, Tregs markers were decreased and IL-15 was increased in reversal reaction and IL-17F, CCL20 and IL-8 in erythema nodosum leprosum, when compared with the respective non-reactional leprosy patients. Additionally, ELISA analysis demonstrated that IL-22, IL-6, IL-10 and anti-PGL-1 antibody levels were significantly higher in the serum of patients when compared with healthy individuals, and IL-10 and anti-PGL-1 antibodies were also increased in the lepromatous pole and side. Together, these results indicate that Th1, Th2 and Th17 are involved in the determination of clinical forms of leprosy and suggest that decreased Tregs activity may be involved in the pathogenesis of reactional events.

  16. Analysis of phytoplasma-responsive sRNAs provide insight into the pathogenic mechanisms of mulberry yellow dwarf disease

    Science.gov (United States)

    Gai, Ying-Ping; Li, Yi-Qun; Guo, Fang-Yue; Yuan, Chuan-Zhong; Mo, Yao-Yao; Zhang, Hua-Liang; Wang, Hong; Ji, Xian-Ling

    2014-06-01

    The yellow dwarf disease associated with phytoplasmas is one of the most devastating diseases of mulberry and the pathogenesis involved in the disease is poorly understood. To analyze the molecular mechanisms mediating gene expression in mulberry-phytoplasma interaction, the comprehensive sRNA changes of mulberry leaf in response to phytoplasma-infection were examined. A total of 164 conserved miRNAs and 23 novel miRNAs were identified, and 62 conserved miRNAs and 13 novel miRNAs were found to be involved in the response to phytoplasma-infection. Meanwhile, target genes of the responsive miRNAs were identified by sequencing of the degradome library. In addition, the endogenous siRNAs were sequenced, and their expression profiles were characterized. Interestingly, we found that phytoplasma infection induced the accumulation of mul-miR393-5p which was resulted from the increased transcription of MulMIR393A, and mul-miR393-5p most likely initiate the biogenesis of siRNAs from TIR1 transcript. Based on the results, we can conclude that phytoplasma-responsive sRNAs modulate multiple hormone pathways and play crucial roles in the regulation of development and metabolism. These responsive sRNAs may work cooperatively in the response to phytoplasma-infection and be responsible for some symptoms in the infected plants.

  17. The Adenovirus E4orf4 Protein Provides a Novel Mechanism for Inhibition of the DNA Damage Response.

    Directory of Open Access Journals (Sweden)

    Anna Brestovitsky

    2016-02-01

    Full Text Available The DNA damage response (DDR is a conglomerate of pathways designed to detect DNA damage and signal its presence to cell cycle checkpoints and to the repair machinery, allowing the cell to pause and mend the damage, or if the damage is too severe, to trigger apoptosis or senescence. Various DDR branches are regulated by kinases of the phosphatidylinositol 3-kinase-like protein kinase family, including ataxia-telangiectasia mutated (ATM and ATM- and Rad3-related (ATR. Replication intermediates and linear double-stranded genomes of DNA viruses are perceived by the cell as DNA damage and activate the DDR. If allowed to operate, the DDR will stimulate ligation of viral genomes and will inhibit virus replication. To prevent this outcome, many DNA viruses evolved ways to limit the DDR. As part of its attack on the DDR, adenovirus utilizes various viral proteins to cause degradation of DDR proteins and to sequester the MRN damage sensor outside virus replication centers. Here we show that adenovirus evolved yet another novel mechanism to inhibit the DDR. The E4orf4 protein, together with its cellular partner PP2A, reduces phosphorylation of ATM and ATR substrates in virus-infected cells and in cells treated with DNA damaging drugs, and causes accumulation of damaged DNA in the drug-treated cells. ATM and ATR are not mutually required for inhibition of their signaling pathways by E4orf4. ATM and ATR deficiency as well as E4orf4 expression enhance infection efficiency. Furthermore, E4orf4, previously reported to induce cancer-specific cell death when expressed alone, sensitizes cells to killing by sub-lethal concentrations of DNA damaging drugs, likely because it inhibits DNA damage repair. These findings provide one explanation for the cancer-specificity of E4orf4-induced cell death as many cancers have DDR deficiencies leading to increased reliance on the remaining intact DDR pathways and to enhanced susceptibility to DDR inhibitors such as E4orf4

  18. Dietary Fructo-Oligosaccharides Attenuate Early Activation of CD4+ T Cells Which Produce both Th1 and Th2 Cytokines in the Intestinal Lymphoid Tissues of a Murine Food Allergy Model.

    Science.gov (United States)

    Tsuda, Masato; Arakawa, Haruka; Ishii, Narumi; Ubukata, Chihiro; Michimori, Mana; Noda, Masanari; Takahashi, Kyoko; Kaminogawa, Shuichi; Hosono, Akira

    2017-11-17

    Fructo-oligosaccharides (FOS) are prebiotic agents with immunomodulatory effects involving improvement of the intestinal microbiota and metabolome. In this study, we investigated the cellular mechanisms through which FOS modulate intestinal antigen-specific CD4+ T cell responses in food allergy, using OVA23-3 mice. OVA23-3 mice were fed an experimental diet containing either ovalbumin (OVA) or OVA and FOS for 1 week. Body weight and mucosal mast cell protease 1 in the serum were measured as the indicator of intestinal inflammation. Single-cell suspensions were prepared from intestinal and systemic lymphoid tissues for cellular analysis. Cytokine production was measured by ELISA. Activation markers and intracellular cytokines in CD4+ T cells were analyzed by flow cytometry. Activated CD4+ T cells were purified to examine cytokine production. Dietary intake of FOS provided moderate protection from the intestinal inflammation induced by the OVA-containing diet. FOS significantly reduced food allergy-induced Th2 cytokine responses in intestinal tissues but not in systemic tissues. FOS decreased OVA diet-induced IFN-γ+IL-4+ double-positive CD4+ T cells and early-activated CD45RBhighCD69+CD4+ T cells in the mesenteric lymph nodes. Furthermore, we confirmed that these CD45RBhighCD69+CD4+ T cells are able to produce high levels of IFN-γ and moderate level of IL-4, IL-10, and IL-13. Dietary intake of FOS during the development of food allergy attenuates the induction of intestinal Th2 cytokine responses by regulating early activation of naïve CD4+ T cells, which produce both Th1 and Th2 cytokines. Our results suggest FOS might be a potential food agent for the prevention of food allergy by modulating oral sensitization to food antigens. © 2017 S. Karger AG, Basel.

  19. Allergies - A T cells perspective in the era beyond the TH1/TH2 paradigm.

    Science.gov (United States)

    Berker, Moritz; Frank, Larissa Johanna; Geßner, Anja Lidwina; Grassl, Niklas; Holtermann, Anne Verena; Höppner, Stefanie; Kraef, Christian; Leclaire, Martin Dominik; Maier, Pia; Messerer, David Alexander Christian; Möhrmann, Lino; Nieke, Jan Philipp; Schoch, Diana; Soll, Dominik; Woopen, Christina Marianne Paulina

    2017-01-01

    Allergic diseases have emerged as a major health care burden, especially in the western hemisphere. They are defined by overshooting reactions of an aberrant immune system to harmless exogenous stimuli. The T H 1/T H 2 paradigm assumes that a dominance of T H 2 cell activation and an inadequate T H 1 cell response are responsible for the development of allergies. However, the characterization of additional T helper cell subpopulations such as T H 9, T H 17, T H 22, T H GM-CSF and their interplay with regulatory T cells suggest further layers of complexity. This review summarizes state-of-the-art knowledge on T cell diversity and their induction, while revisiting the T H 1/T H 2 paradigm. With respect to these numerous contributors, it offers a new perspective on the pathogenesis of asthma, allergic rhinitis (AR) and atopic dermatitis (AD) incorporating recent discoveries in the field of T cell plasticity. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Production of IL-16 correlates with CD4+ Th1 inflammation and phosphorylation of axonal cytoskeleton in multiple sclerosis lesions

    Directory of Open Access Journals (Sweden)

    Cai Juan

    2006-05-01

    Full Text Available Abstract Background Multiple sclerosis (MS is a central nervous system-specific autoimmune, demyelinating and neurodegenerative disease. Infiltration of lesions by autoaggressive, myelin-specific CD4+Th1 cells correlates with clinical manifestations of disease. The cytokine IL-16 is a CD4+ T cell-specific chemoattractant that is biased towards CD4+ Th1 cells. IL-16 precursor is constitutively expressed in lymphocytes and during CD4+ T cell activation; active caspase-3 cleaves and releases C-terminal bioactive IL-16. Previously, we used an animal model of MS to demonstrate an important role for IL-16 in regulation of autoimmune inflammation and subsequent axonal damage. This role of IL-16 in MS is largely unexplored. Here we examine the regulation of IL-16 in relation to CD4+ Th1 infiltration and inflammation-related changes of axonal cytoskeleton in MS lesions. Methods We measured relative levels of IL-16, active caspase-3, T-bet, Stat-1 (Tyr 701, and phosphorylated NF(M+H, in brain and spinal cord lesions from MS autopsies, using western blot analysis. We examined samples from 39 MS cases, which included acute, subacute and chronic lesions, as well as adjacent, normal-appearing white and grey matter. All samples were taken from patients with relapsing remitting clinical disease. We employed two-color immunostaining and confocal microscopy to identify phenotypes of IL-16-containing cells in frozen tissue sections from MS lesions. Results We found markedly increased levels of pro- and secreted IL-16 (80 kD and 22 kD, respectively in MS lesions compared to controls. Levels of IL-16 peaked in acute, diminished in subacute, and were elevated again in chronic active lesions. Compared to lesions, lower but still appreciable IL-6 levels were measured in normal-appearing white matter adjacent to active lesions. Levels of IL-16 corresponded to increases in active-caspase-3, T-bet and phosphorylated Stat-1. In MS lesions, we readily observed IL-16

  1. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery.

    Science.gov (United States)

    Yu, Jicheng; Zhang, Yuqi; Ye, Yanqi; DiSanto, Rocco; Sun, Wujin; Ranson, Davis; Ligler, Frances S; Buse, John B; Gu, Zhen

    2015-07-07

    A glucose-responsive "closed-loop" insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report a novel glucose-responsive insulin delivery device using a painless microneedle-array patch ("smart insulin patch") containing glucose-responsive vesicles (GRVs; with an average diameter of 118 nm), which are loaded with insulin and glucose oxidase (GOx) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioreduction under hypoxic conditions. The local hypoxic microenvironment caused by the enzymatic oxidation of glucose in the hyperglycemic state promotes the reduction of HS-HA, which rapidly triggers the dissociation of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chemically induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy.

  2. Integration of Known DNA, RNA and Protein Biomarkers Provides Prediction of Anti-TNF Response in Rheumatoid Arthritis

    DEFF Research Database (Denmark)

    Folkersen, Lasse; Brynedal, Boel; Marcela Diaz-Gallo, Lina

    2016-01-01

    to test the claim that the current state-of-the-art precision medicine will benefit RA patients. METHODS: We collected 451 blood samples from 61 healthy individuals and 185 RA patients initiating treatment, before treatment initiation and at a 3 month follow-up time. All samples were subjected to high...... and replication. Taking advantage of this we surveyed the current state-of-the-art of drug-response stratification in RA, and identified a small set of previously published biomarkers available in peripheral blood which predicts clinical response to TNF blockade in this independent cohort....

  3. TH1 and TH2 cytokine data in insulin secretagogues users newly diagnosed with breast cancer

    Directory of Open Access Journals (Sweden)

    Zachary A.P. Wintrob

    2017-04-01

    Full Text Available Stimulation of insulin production by insulin secretagogue use may impact T helper cells’ cytokine production. This dataset presents the relationship between baseline insulin secretagogues use in women diagnosed with breast cancer and type 2 diabetes mellitus, the T-helper 1 and 2 produced cytokine profiles at the time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis evaluating the relationship between T-helper cytokines stratified by of insulin secretagogues use and controls is also provided.

  4. Review and Response to the Final Report of the National Black Health Providers Task Force on High Blood Pressure Education and Control.

    Science.gov (United States)

    Public Health Service (DHHS), Rockville, MD.

    This report presents the National Heart, Lung, and Blood Institute's (NHLBI) review of and response to the final report of the National Black Health Providers Task Force on High Blood Pressure Education and Control. The response includes a statement of NHLBI's involvement in health research, and descriptions of what steps can be taken to solve the…

  5. EEG derivations providing auditory steady-state responses with high signal-to-noise ratios in infants.

    NARCIS (Netherlands)

    Reijden, C.S. van der; Mens, L.H.M.; Snik, A.F.M.

    2005-01-01

    OBJECTIVE: To identify EEG derivations that yield high signal-to-noise ratios (SNRs) of the auditory steady-state response (ASSR) in infants aged 0 to 5 months. DESIGN: The ASSR was recorded simultaneously from 10 EEG derivations in a monopolar montage in 20 sleeping infants. Stimuli were tones of

  6. Serum Th1, Th2 and Th17 cytokine profiles and alpha-enolase levels in recurrent aphthous stomatitis.

    Science.gov (United States)

    Ozyurt, Kemal; Celik, Ahmet; Sayarlıoglu, Mehmet; Colgecen, Emine; Incı, Rahime; Karakas, Tuba; Kelles, Mehmet; Cetin, Gozde Y

    2014-10-01

    All aspects of aetiopathogenesis of recurrent aphthous stomatitis (RAS) have not been elucidated. RAS and Behçet's disease (BD) have clinical and immunological characteristics in common. Although T17 cytokines and alpha-enolase have been shown to play effective roles in BD and many other autoinflammatory diseases recently, their roles in RAS have not been studied extensively. In the present study, we investigated levels of several Th1, Th2 and Th17 pathways related cytokines and alpha-enolase to elucidate pathogenesis of RAS and to obtain data about possible treatment alternatives for the condition. Serum interleukin-1, interleukin-13, interleukin-17, interleukin-18, interferon gamma and alpha-enolase levels in 24 patients with RAS, 30 patients with BD and 20 healthy controls were measured. Serum interleukin-1, interleukin-13, interleukin-17, interleukin-18, interferon gamma and alpha-enolase levels were higher in patients with RAS and patients with BD than in healthy controls (P < 0.005). Like Th1 and Th2 cells, Th17 cells were found to be effective in pathogenesis of RAS. In addition, alpha-enolase, the levels of which were high, may play an important role in etio-pathogenesis of RAS. Further studies to be designed in the light of these findings are required to shed light on pathogenesis and treatment of the condition. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Interleukin-10 deficiency impairs regulatory T cell-derived neuropilin-1 functions and promotes Th1 and Th17 immunity.

    Science.gov (United States)

    Wang, Shimin; Gao, Xiang; Shen, Guobo; Wang, Wei; Li, Jingyu; Zhao, Jingyi; Wei, Yu-Quan; Edwards, Carl K

    2016-04-14

    Regulatory T cells (Tregs) expand in peripheral lymphoid organs and can produce immunosuppressive cytokines to support tumor growth. IL-10 abrogation efficiently induces Treg formation but dampens tumoral neuropilin-1 (Nrp-1) Treg signaling, which simultaneously augments Th1 and Th17 immunity. These effects are associated with the plasticity and stability of Tregs and effector T cell functions that can limit tumorigenesis. Within the tumor microenvironment, there appears to be a "mutual antagonism" between immunoenhancement and immunosuppression mechanisms, eventually leading to decreased metastasis. In contrast, tumor progression is paralleled by a reduction in Nrp-1-producing Tregs controlled by the IL-10 and TGF-β1 levels. However, Th1, Th17 and Treg immunity is primarily regulated by IL-10 or Nrp-1 and not TGF-β1 except when combined with IL-10. These results emphasize the important implications for the therapeutic use of Tregs. The number of Treg cells must be maintained in a healthy and dynamic homeostatic range to prevent malignant diseases. Moreover, Treg-mediated immunosuppression can be limited by reducing tumor-derived Treg Nrp-1 levels.

  8. In vivo Th1 and Th2 cytokine modulation effects of Rhodiola rosea standardised solution and its major constituent, salidroside.

    Science.gov (United States)

    Lin, Shih-Shen Chou; Chin, Lengsu William; Chao, Pei-Chun; Lai, Ya-Yun; Lin, Long-Yau; Chou, Ming-Yung; Chou, Ming-Chih; Wei, James Cheng-Chung; Yang, Chi-Chiang

    2011-11-01

    Although Rhodiola rosea (L.) is used widely and disseminated in Oriental medicine, its in vivo effects on cytokine modulation remain unclear. Among the biologically active components of Rhodiola rosea, salidroside was suggested to be the most active compound. The objectives of this study were to assess the toxicity and cytokine modulation effects of Rhodiola rosea standardised solution (RRSS) and salidroside. Quantitative high pressure liquid chromatography (HPLC) analysis determined the content of salidroside in RRSS to be 4.39% (w/v). Groups of Balb/c mice were fed daily with different doses of RRSS or salidroside, with CAPE or distilled water used as positive and negative controls, respectively. The acute and subacute toxicity tests did not reveal weight differences, pathological changes, or abnormalities in liver or kidney function indices among the treated groups. Ovalbumin-primed mouse cytokine assays demonstrated that both T helper (Th1) (IL-2 and IFN-γ) and Th2 (IL-4 and IL-10) cytokines were significantly increased by feeding with RRSS in a dose- and time-dependent manner (p < 0.05). Moreover, the cytokine modulation effects of salidroside were less prominent than that of RRSS treatment and not dose-dependent. These findings suggest that increased secretion of both Th1- and Th2-pattern cytokines can be achieved with RRSS and salidroside treatment. Copyright © 2011 John Wiley & Sons, Ltd.

  9. The Microbial Metabolite Butyrate Induces Expression of Th1-Associated Factors in CD4+ T Cells

    Directory of Open Access Journals (Sweden)

    Meike Kespohl

    2017-08-01

    Full Text Available Short-chain fatty acids (SCFAs, which are generated by the bacterial fermentation of dietary fibers, promote expansion of regulatory T cells (Tregs. Potential therapeutic value of SCFAs has been recently highlighted in the experimental models of T cell-mediated autoimmunity and allergic inflammation. These studies suggest that physiological intestinal concentrations of SCFAs within the millimolar range are crucial for dampening inflammation-mediated processes. Here, we describe opposing effects of SCFAs on T cell-mediated immune responses. In accordance with published data, lower butyrate concentrations facilitated differentiation of Tregs in vitro and in vivo under steady-state conditions. In contrast, higher concentrations of butyrate induced expression of the transcription factor T-bet in all investigated T cell subsets resulting in IFN-γ-producing Tregs or conventional T cells. This effect was mediated by the inhibition of histone deacetylase activity and was independent of SCFA-receptors FFA2 and FFA3 as well as of Na+-coupled SCFA transporter Slc5a8. Importantly, while butyrate was not able to induce the generation of Tregs in the absence of TGF-β1, the expression of T-bet and IFN-γ was triggered upon stimulation of CD4+ T cells with this SCFA alone. Moreover, the treatment of germ-free mice with butyrate enhanced the expression of T-bet and IFN-γ during acute colitis. Our data reveal that, depending on its concentration and immunological milieu, butyrate may exert either beneficial or detrimental effects on the mucosal immune system.

  10. The CC-chemokine receptor 5 (CCR5) is a marker of, but not essential for the development of human Th1 cells

    DEFF Research Database (Denmark)

    Odum, Niels; Bregenholt, S; Eriksen, K W

    1999-01-01

    The CC-chemokine receptor 5 (CCR5) has recently been described as a surface marker of human T cells producing type 1 (Th1) cytokines. Here we confirm that CCR5 is expressed on human Th1 but not on Th2 T-cell clones. Using intracellular cytokine staining, we show that alloantigen specific CD4+ T....... These results were similar to those obtained from alloantigen specific CD4+ T-cell lines derived from CCR5 expressing individuals. An enzyme-linked immunoabsorbent assay (ELISA) confirmed that the Th1 cytokine-positive cells from the CCR5-deficient individual were able to produce equal amounts of cytokines when...

  11. Lipopolysaccharide-induced expression of Th1/Th2 cytokines in whole neonatal cord and adult blood: role of nuclear factor-kappa B and p38 MAPK.

    Science.gov (United States)

    Koch, Lutz; Fritzsching, Benedikt; Frommhold, David; Poeschl, Johannes

    2011-01-01

    Sepsis continues to be a leading cause of morbidity and mortality in newborns. As both nuclear factor-kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) appear to be critical mediators in inflammatory response, we studied the effects of lipopolysaccharide (LPS) on expression and function of NF-κB and p38 MAPK in whole neonatal cord and adult blood. Th1/Th2 cytokine concentrations and phosphorylation of NF-κB and p38 MAPK were determined by flow-cytometric analysis. Tumor necrosis factor-alpha (TNF-α), IL-6, and IL-10 concentrations were significantly elevated in supernatants of neonatal and adult blood after LPS stimulation for 4 h. IFN-γ, IL-4, and IL-2 showed no significant alterations. Furthermore, TNF-α concentrations were significantly higher in adult compared to neonatal blood after LPS stimulation. Stimulation with LPS resulted in significantly decreased activation of p38 MAPK in neonatal blood, whereas NF-κB showed no difference. Following inhibition of p38 MAPK with the specific inhibitor SB-202190, levels of TNF-α and IL-6 significantly decreased in neonatal and adult blood, whereas pharmacological inhibition of NF-κB with SC-514 showed no significant effect on cytokine expression. We conclude that p38 MAPK phosphorylation is crucially involved in LPS activation and could explain the differences in early cytokine response between neonatal and adult blood. Copyright © 2010 S. Karger AG, Basel.

  12. Legal responsibilities of physicians when making participation decisions in athletes with cardiac disorders: Do guidelines provide a solid legal footing?

    Science.gov (United States)

    Panhuyzen-Goedkoop, Nicole M; Smeets, Joep L R M

    2014-08-01

    Safe sports participation involves protecting athletes from injury and life-threatening situations. Preparticipation cardiovascular screening (PPS) in athletes is intended to prevent exercise-related sudden cardiac death by medical management of athletes at risk, which may include disqualification from sports participation. The screening physician relies on current guidelines and expert recommendations for management and decision-making. There is concern about false-positive screening results and wrongly grounding an athlete. Similarly, there is a concern about false-negative screening results and athletes participating with potentially lethal disorders. Who is legally responsible if an athlete suddenly dies after a proper PPS resulting in low risk? Several consensus documents based on expert opinion describe only a few lines on legal responsibilities in eligibility screening and disqualification decision-making in athletes. This article discusses legal responsibilities and concerns in eligibility decision-making for physicians. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  13. Regulation-Structured Dynamic Metabolic Model Provides a Potential Mechanism for Delayed Enzyme Response in Denitrification Process

    Energy Technology Data Exchange (ETDEWEB)

    Song, Hyun-Seob; Thomas, Dennis G.; Stegen, James C.; Li, Minjing; Liu, Chongxuan; Song, Xuehang; Chen, Xingyuan; Fredrickson, Jim K.; Zachara, John M.; Scheibe, Timothy D.

    2017-09-29

    In a recent study of denitrification dynamics in hyporheic zone sediments, we observed a significant time lag (up to several days) in enzymatic response to the changes in substrate concentration. To explore an underlying mechanism and understand the interactive dynamics between enzymes and nutrients, we developed a trait-based model that associates a community’s traits with functional enzymes, instead of typically used species guilds (or functional guilds). This enzyme-based formulation allows to collectively describe biogeochemical functions of microbial communities without directly parameterizing the dynamics of species guilds, therefore being scalable to complex communities. As a key component of modeling, we accounted for microbial regulation occurring through transcriptional and translational processes, the dynamics of which was parameterized based on the temporal profiles of enzyme concentrations measured using a new signature peptide-based method. The simulation results using the resulting model showed several days of a time lag in enzymatic responses as observed in experiments. Further, the model showed that the delayed enzymatic reactions could be primarily controlled by transcriptional responses and that the dynamics of transcripts and enzymes are closely correlated. The developed model can serve as a useful tool for predicting biogeochemical processes in natural environments, either independently or through integration with hydrologic flow simulators.

  14. Rola subpopulacji limfocytów pomocniczych Th1, Th17 i Treg w patogenezie reumatoidalnego zapalenia stawów z uwzględnieniem przeciwzapalnego działania cytokin Th1

    Directory of Open Access Journals (Sweden)

    Agata Kosmaczewska

    2011-06-01

    Full Text Available W patogenezie reumatoidalnego zapalenia stawów (RZS szczególną rolę przypisuje się zaburzeniom w funkcjonowaniu układu odpornościowego. Przewlekły charakter zapalenia w stawach sugeruje, że regulacja ze strony układu odpornościowego jest zaburzona, co wiąże się z nadmiernie rozwiniętą odpowiedzią zapalną, której towarzyszą nieprawidłowe mechanizmy kontroli zapalenia. Zaburzenia immunologiczne nie ograniczają się jedynie do miejsc zapalenia, ale mają również charakter systemowy i obejmują głównie komórki jednojądrzaste krwi obwodowej (PBMC, wydzielające w nieprawidłowych ilościach cytokiny pro- i przeciwzapalne. Limfocyty T pomocnicze (Th mogą się różnicować w zależności od środowiska cytokinowego w komórki Th1, Th2, Th17 lub Treg. Aktywna postać RZS może być wynikiem przesunięcia równowagi układu odpornościowego w kierunku subpopulacji limfocytów T prozapalnych (głównie Th17 na niekorzyść regulatorowych komórek działających przeciwzapalnie (Treg. Wykazano, że zaburzenia wytwarzania cytokin Th1 (IL-2 i IFN-gamma, stwierdzane w przebiegu RZS, sprzyjają zwiększonemu wytwarzaniu IL-17 i infiltracji tkanek w miejscu zapalenia komórkami Th17. Najnowsze badania dowodzą, że cytokiny Th1 o udowodnionym działaniu prozapalnym mogą odgrywać ważną rolę w utrzymaniu równowagi między limfocytami Treg a Th17 poprzez promowanie różnicowania limfocytów Th w kierunku Treg. W pracy przedstawiono także wpływ TNF-alfa i jego blokady na populacje limfocytów Th u chorych na RZS.

  15. Recombinant ESAT-6-CFP10 Fusion Protein Induction of Th1/Th2 Cytokines and FoxP3 Expressing Treg Cells in Pulmonary TB.

    Directory of Open Access Journals (Sweden)

    Dolly Jackson-Sillah

    Full Text Available Early secretory antigenic target 6 (ESAT-6 and culture filtrate protein 10 (CFP-10 are Mycobacterium tuberculosis (Mtb-specific antigens that are secreted by actively metabolising bacteria and contribute to the virulence of the bacteria. Their ability to induce Treg and Th2 responses, particularly during the first two weeks of treatment, has not been comprehensively examined to date. The purpose of this work was to characterise Th1, Th2 and Treg responses to rESAT-6-CFP10 fusion protein in TB patients before and during the intensive phase of treatment and in healthy M.bovis BCG vaccinated donors.Forty-six newly diagnosed, HIV-negative, smear-positive pulmonary TB patients and 20 healthy donors were recruited in the UK and Ghana. Their peripheral blood mononuclear cells (PBMC were used in ex vivo ELISPOT and in vitro cultures to identify immunological parameters of interest.The study confirmed that protective immune responses to rESAT-6-CFP10 are impaired in active TB but improved during treatment: circulating antigen-specific IL-4-producing T-cells were increased in untreated TB but declined by two weeks of treatment while the circulating antigen-specific IFN-γ producing T cells which showed a transient rise at one week of treatment, persisted at baseline levels at two months of treatment. In vitro T cell proliferation and IFN-γ production were reduced, while IL-4 and CD4(+FoxP3(+CD25(hi cell expression were increased in response to rESAT-6-CFP10 fusion protein in untreated TB. These responses were reversed during early treatment of TB.These observations support further investigations into the possible utility of these parameters as markers of active disease and favourable treatment outcomes.

  16. Th1-stimulatory polyproteins of soluble Leishmania donovani promastigotes ranging from 89.9 to 97.1 kDa offers long-lasting protection against experimental visceral leishmaniasis.

    Science.gov (United States)

    Kumari, Shraddha; Samant, Mukesh; Misra, Pragya; Khare, Prashant; Sisodia, Brijesh; Shasany, Ajit K; Dube, Anuradha

    2008-10-23

    Our earlier studies identified a fraction (F2) of Leishmania donovani soluble promastigote antigen belonging to 97.4-68 kDa for its ability to stimulate Th1-type cellular responses in cured visceral leishmaniasis (VL) patients as well as in cured hamsters. A further fractionation of F2-fraction into seven subfractions (F2.1-F2.7) and re-assessment for their immunostimulatory responses revealed that out of these, only four (F2.4-F2.7) belonging to 89.9-97.1 kDa, stimulated remarkable Th1-type cellular responses either individually or in a pooled form (P4-7). In this study these potential subfractions were further assessed for their prophylactic potential in combination with BCG against L. donovani challenge in hamsters. Optimum parasite inhibition ( approximately 99%) was obtained in hamsters vaccinated with pooled subfractions and they survived for 1 year. The protection was further supported by remarkable lymphoproliferative, IFN-gamma and IL-12 responses along with profound delayed type hypersensitivity and increased levels of Leishmania-specific IgG2 antibody as observed on days 45, 90 and 120 post-challenge suggesting that a successful subunit vaccine against VL may require multiple Th1-immunostimulatory proteins. MALDI-TOF-MS/MS analysis of these subfractions further revealed that of the 19 identified immunostimulatory proteins, Elongation factor-2, p45, Heat shock protein-70/83, Aldolase, Enolase, Triosephosphate isomerase, Disulfideisomerase and Calreticulin were the major ones in these subfractions.

  17. Characterization of glycolytic enzymes--rAldolase and rEnolase of Leishmania donovani, identified as Th1 stimulatory proteins, for their immunogenicity and immunoprophylactic efficacies against experimental visceral leishmaniasis.

    Science.gov (United States)

    Gupta, Reema; Kumar, Vikash; Kushawaha, Pramod Kumar; Tripathi, Chandradev Pati; Joshi, Sumit; Sahasrabuddhe, Amogh Anant; Mitra, Kalyan; Sundar, Shyam; Siddiqi, Mohammad Imran; Dube, Anuradha

    2014-01-01

    Th1 immune responses play an important role in controlling Visceral Leishmaniasis (VL) hence, Leishmania proteins stimulating T-cell responses in host, are thought to be good vaccine targets. Search of such antigens eliciting cellular responses in Peripheral blood mononuclear cells (PBMCs) from cured/exposed/Leishmania patients and hamsters led to the identification of two enzymes of glycolytic pathway in the soluble lysate of a clinical isolate of Leishmania donovani--Enolase (LdEno) and aldolase (LdAld) as potential Th1 stimulatory proteins. The present study deals with the molecular and immunological characterizations of LdEno and LdAld. The successfully cloned and purified recombinant proteins displayed strong ability to proliferate lymphocytes of cured hamsters' along with significant nitric-oxide production and generation of Th1-type cytokines (IFN-γ and IL-12) from stimulated PBMCs of cured/endemic VL patients. Assessment of their prophylactic potentials revealed ∼ 90% decrease in parasitic burden in rLdEno vaccinated hamsters against Leishmania challenge, strongly supported by an increase in mRNA expression levels of iNOS, IFN-γ, TNF-α and IL-12 transcripts along with extreme down-regulation of TGF-β, IL-4 and IL-10. However, animals vaccinated with rLdAld showed comparatively lesser prophylactic efficacy (∼ 65%) with inferior immunological response. Further, with a possible implication in vaccine design against VL, identification of potential T-cell