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Sample records for th2 dominant microenvironment

  1. Regulatory T Cells Control Th2-Dominant Murine Autoimmune Gastritis1

    Science.gov (United States)

    Harakal, Jessica; Rival, Claudia; Qiao, Hui; Tung, Kenneth S.

    2016-01-01

    Pernicious anemia and gastric carcinoma are serious sequelae of autoimmune gastritis (AIG). Our study indicates that in adult C57BL/6 DEREG mice expressing a transgenic diphtheria toxin receptor under the Foxp3 promoter, transient Treg cell depletion results in long-lasting AIG associated with both H+K+ATPase and intrinsic factor autoantibody responses. Although functional Treg cells emerge over time during AIG occurrence, the effector T cells rapidly become less susceptible to Treg cell-mediated suppression. While previous studies have implicated dysregulated Th1 responses in AIG pathogenesis, eosinophils have been detected in gastric biopsies from patients with AIG. Indeed, AIG in DEREG mice is associated with strong Th2 responses, including dominant IgG1 autoantibodies, elevated serum IgE, increased Th2 cytokine production, and eosinophil infiltration in the stomach draining lymph nodes. Additionally, the stomachs exhibit severe mucosal and muscular hypertrophy, parietal cell loss, mucinous epithelial cell metaplasia, and massive eosinophilic inflammation. Notably, the Th2 responses and gastritis severity are significantly ameliorated in IL-4- or eosinophil-deficient mice. Furthermore, expansion of both Th2-promoting IRF4+PD-L2+ dendritic cells and ILT3+ rebounded Treg cells were detected after transient Treg cell depletion. Collectively, these data suggest that Treg cells maintain physiological tolerance to clinically relevant gastric autoantigens, and Th2 responses can be a pathogenic mechanism in autoimmune gastritis. PMID:27259856

  2. Aerobic Exercise Attenuated Bleomycin-Induced Lung Fibrosis in Th2-Dominant Mice.

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    Adilson Santos Andrade-Sousa

    Full Text Available The aim of this study was to investigate the effect of aerobic exercise (AE in reducing bleomycin-induced fibrosis in mice of a Th2-dominant immune background (BALB/c.BALB/c mice were distributed into: sedentary, control (CON, Exercise-only (EX, sedentary, bleomycin-treated (BLEO and bleomycin-treated+exercised (BLEO+EX; (n = 8/group. Following treadmill adaptation, 15 days following a single, oro-tracheal administration of bleomycin (1.5U/kg, AE was performed 5 days/week, 60min/day for 4 weeks at moderate intensity (60% of maximum velocity reached during a physical test and assessed for pulmonary inflammation and remodeling, and cytokine levels in bronchoalveolar lavage (BAL.At 45 days post injury, compared to BLEO, BLEO+EX demonstrated reduced collagen deposition in the airways (p<0.001 and also in the lung parenchyma (p<0.001. In BAL, a decreased number of total leukocytes (p<0.01, eosinophils (p<0.001, lymphocytes (p<0.01, macrophages (p<0.01, and neutrophils (p<0.01, as well as reduced pro-inflammatory cytokines (CXCL-1; p<0.01, (IL-1β; p<0.001, (IL-5; p<0.01, (IL-6; p<0.001, (IL-13; p<0.01 and pro-fibrotic growth factor IGF-1 (p<0.001 were observed. Anti-inflammatory cytokine IL-10 was increased (p<0.001.AE attenuated bleomycin-induced collagen deposition, inflammation and cytokines accumulation in the lungs of mice with a predominately Th2-background suggesting that therapeutic AE (15-44 days post injury attenuates the pro-inflammatory, Th2 immune response and fibrosis in the bleomycin model.

  3. Th2 dominance in nasal mucosa in patients with Wegener’s granulomatosis

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    Balding, C E J; Howie, A J; Drake-Lee, A B; Savage, C O S

    2001-01-01

    Wegener's granulomatosis initially affects upper respiratory tract organs including the nasal mucosa in more than 90% of patients. The inflammation is typically granulomatous with associated vasculitis. T lymphocytes are usually a prominent component of the leucocyte infiltrate. Previous studies using peripheral blood T cells have implicated IFN-γ rich Th1-type responses. This study addressed the cytokine milieu in nasal mucosa from 10 patients with active Wegener's granulomatosis using immunohistochemistry. Increased levels of CD3+ T cells and eosinophils were present compared with normal and disease controls. There was increased expression of IL-4, down-regulation of IL-2 and no detectable IFN-γ. There was increased expression of the chemokine receptor CCR3 by infiltrating cells, consistent with an IL-4 dominant, Th2-biased response. In contrast, renal biopsy tissue from 10 patients with active Wegener's granulomatosis showed expression of IL-2 and IL-4. The Th2-type environment within nasal mucosa, often the initial site of disease activity in Wegener's, is consistent with a local allergic response in these patients. PMID:11529927

  4. Early exposure of infants to GI nematodes induces Th2 dominant immune responses which are unaffected by periodic anthelminthic treatment.

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    Victoria J Wright

    Full Text Available We have previously shown a reduction in anaemia and wasting malnutrition in infants <3 years old in Pemba Island, Zanzibar, following repeated anthelminthic treatment for the endemic gastrointestinal (GI nematodes Ascaris lumbricoides, hookworm and Trichuris trichiura. In view of the low intensity of worm infections in this age group, this was unexpected, and it was proposed that immune responses to the worms rather than their direct effects may play a significant role in morbidity in infants and that anthelminthic treatment may alleviate such effects. Therefore, the primary aims of this study were to characterise the immune response to initial/early GI nematode infections in infants and the effects of anthelminthic treatment on such immune responses. The frequency and levels of Th1/Th2 cytokines (IL-5, IL-13, IFN-gamma and IL-10 induced by the worms were evaluated in 666 infants aged 6-24 months using the Whole Blood Assay. Ascaris and hookworm antigens induced predominantly Th2 cytokine responses, and levels of IL-5 and IL-13 were significantly correlated. The frequencies and levels of responses were higher for both Ascaris positive and hookworm positive infants compared with worm negative individuals, but very few infants made Trichuris-specific cytokine responses. Infants treated every 3 months with mebendazole showed a significantly lower prevalence of infection compared with placebo-treated controls at one year following baseline. At follow-up, cytokine responses to Ascaris and hookworm antigens, which remained Th2 biased, were increased compared with baseline but were not significantly affected by treatment. However, blood eosinophil levels, which were elevated in worm-infected children, were significantly lower in treated children. Thus the effect of deworming in this age group on anaemia and wasting malnutrition, which were replicated in this study, could not be explained by modification of cytokine responses but may be related to

  5. Mice deficient in MyD88 Develop a Th2-dominant response and severe pathology in the upper genital tract following Chlamydia muridarum infection.

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    Chen, Lili; Lei, Lei; Chang, Xiaotong; Li, Zhihong; Lu, Chunxue; Zhang, Xiaoyun; Wu, Yimou; Yeh, I-Tien; Zhong, Guangming

    2010-03-01

    MyD88, a key adaptor molecule required for many innate immunity receptor-activated signaling pathways, was evaluated in a Chlamydia muridarum urogenital tract infection model. Compared with wild-type mice, MyD88 knockout (KO) mice failed to produce significant levels of inflammatory cytokines in the genital tract during the first week of chlamydial infection. MyD88 KO mice developed a Th2-dominant whereas wild-type mice developed a Th1/Th17-dominant immune response after chlamydial infection. Despite the insufficient production of early inflammatory cytokines and lack of Th1/Th17-dominant adaptive immunity, MyD88 KO mice appeared to be as resistant to chlamydial intravaginal infection as wild-type mice based on the number of live organisms recovered from vaginal samples. However, significantly high numbers of chlamydial organisms were detected in the upper genital tract tissues of MyD88 KO mice. Consequently, MyD88 KO mice developed more severe pathology in the upper genital tract. These results together have demonstrated that MyD88-dependent signaling pathway is not only required for inflammatory cytokine production in the early phase of host response to chlamydial infection but also plays a critical role in the development of Th1/Th17 adaptive immunity, both of which may be essential for limiting ascending infection and reducing pathology of the upper genital tract by chlamydial organisms.

  6. Desert dust induces TLR signaling to trigger Th2-dominant lung allergic inflammation via a MyD88-dependent signaling pathway

    International Nuclear Information System (INIS)

    He, Miao; Ichinose, Takamichi; Song, Yuan; Yoshida, Yasuhiro; Bekki, Kanae; Arashidani, Keiichi; Yoshida, Seiichi; Nishikawa, Masataka; Takano, Hirohisa; Shibamoto, Takayuki; Sun, Guifan

    2016-01-01

    Asian sand dust (ASD) is known to exacerbate asthma, although its mechanism is not yet well understood. In this study, when the effects on inflammatory response by LPS present in ASD was investigated by measuring the gene expression of cytokines and chemokines in RAW264.7 cells treated with ASD and/or polymyxin B (PMB), the ASD effects were attenuated by PMB, but not completely. When an in vitro study was performed using bone marrow-derived macrophages (BMDMs) from WT, TLR2 −/− , TLR4 −/− , and MyD88 −/− BALB/c mice and BMDMs from WT, TLR2 −/− , TLR4 −/− , TLR2/4 −/− , TLR7/9 −/− , and MyD88 −/− C57BL/6J mice, cytokine (IL-6, IL-12) production in BMDMs was higher in ASD-stimulated TLR2 −/− cells than in TLR4 −/− cells, whereas it was lower or undetectable in TLR2/4 −/− and MyD88 −/− cells. These results suggest that ASD causes cytokine production predominantly in a TLR4/MyD88-dependent pathway. When WT and TLRs 2 −/− , 4 −/− , and MyD88 −/− BALB/c mice were intratracheally challenged with OVA and/or ASD, ASD caused exacerbation of lung eosinophilia along with Th2 cytokine and eosinophil-relevant chemokine production. Serum OVA-specific IgE and IgG1 similar to WT was observed in TLRs 2 −/− , 4 −/− mice, but not in MyD88 −/− mice. The Th2 responses in TLR2 −/− mice were attenuated remarkably by PMB. These results indicate that ASD exacerbates lung eosinophilia in a MyD88-dependent pathway. TLRs 2 and 4 signaling may be important in the increase in lung eosinophilia. Also, the TLR4 ligand LPS and TLR2 ligand like β-glucan may be strong candidates for exacerbation of lung eosinophilia. - Highlights: • ASD enhanced Th2 response in TLR2 −/− , TLR4 −/− and WT mice, but not in MyD88 −/− . • Th2 responses in TLR2 −/− mice were attenuated by LPS inhibitor polymyxin B. • TLR2 and TLR4 signaling is important in allergic lung disease aggravation by ASD. • MyD88 is the key

  7. Tumor-associated macrophages in oral premalignant lesions coexpress CD163 and STAT1 in a Th1-dominated microenvironment

    International Nuclear Information System (INIS)

    Mori, Kazumasa; Haraguchi, Shigeki; Hiori, Miki; Shimada, Jun; Ohmori, Yoshihiro

    2015-01-01

    Tumor-associated macrophages (TAMs) are implicated in the growth, invasion and metastasis of various solid tumors. However, the phenotype of TAMs in premalignant lesions of solid tumors has not been clarified. In the present study, we identify the phenotype of TAMs in leukoplakia, an oral premalignant lesion, by immunohistochemical analysis and investigate the involvement of infiltrated T cells that participate in the polarization of TAMs. The subjects included 30 patients with oral leukoplakia and 10 individuals with normal mucosa. Hematoxylin and eosin slides were examined for the histological grades, and immunohistochemical analysis was carried out using antibodies against CD68 (pan-MΦ), CD80 (M1 MΦ), CD163 (M2 MΦ), CD4 (helper T cells: Th), CD8 (cytotoxic T cells), CXCR3, CCR5 (Th1), CCR4 (Th2), signal transducer and activator of transcription (STAT1), phosphorylated STAT1 (pSTAT1) and chemokine CXCL9. The differences in the numbers of positively stained cells among the different histological grades were tested for statistical significance using the Kruskal-Wallis test. Correlations between different types of immune cells were determined using Spearman’s rank analysis. An increase in the rate of CD163 + TAM infiltration was observed in mild and moderate epithelial dysplasia, which positively correlated with the rate of intraepithelial CD4 + Th cell infiltration. Although CCR4 + cells rarely infiltrated, CXCR3 + and CCR5 + cells were observed in these lesions. Cells positive for STAT1 and chemokine CXCL9, interferon- (IFN)-induced gene products, and pSTAT1 were also observed in the same lesions. Double immunofluorescence staining demonstrated that the cells that were positive for CD163 were also positive for STAT1. CD163 + TAMs in oral premalignant lesions coexpress CD163 and STAT1, suggesting that the TAMs in oral premalignant lesions possess an M1 phenotype in a Th1-dominated micromilieu

  8. Innate immunological function of TH2 cells in vivo

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    Th2 cells produce IL-13 when stimulated by papain or house dust mites (HDM) and induce eosinophilic inflammation. This innate response of cells of the adaptive immune system is dependent on IL-33-, not T cell receptor-, based stimulation. While type 2 innate lymphoid cells (ILC2s) are the dominant ...

  9. How to deal with polarized Th2 cells: exploring the Achilles' heel

    NARCIS (Netherlands)

    Smits, H. H.; Hilkens, C. M.; Kalinski, P.; Kapsenberg, M. L.; Wierenga, E. A.

    2001-01-01

    The central effector cells in the pathogenesis of atopic allergic diseases are type 2 T helper (Th2) cells, which display an aberrant cytokine profile dominated by type 2 cytokines. Initial reports from mouse studies indicated that established and committed Th2 cells are stable and unsusceptible to

  10. Mina: a Th2 response regulator meets TGFβ.

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    Pillai, Meenu R; Lian, Shangli; Bix, Mark

    2014-12-01

    The JmjC protein Mina is an important immune response regulator. Classical forward genetics first discovered its immune role in 2009 in connection with the development of T helper 2 (Th2) cells. This prompted investigation into Mina's role in the two best-studied contexts where Th2 responses are essential: atopic asthma and helminth expulsion. In work focused on a mouse model of atopic asthma, Mina deficiency was found to ameliorate airway hyper-resistance and pulmonary inflammation. And, in a case-control study genetic variation at the human MINA locus was found to be associated with the development of childhood atopic asthma. Although the underlying cellular and molecular mechanism of Mina's involvement in pulmonary inflammation remains unknown, our recent work on parasitic helminth expulsion suggests the possibility that, rather than T cells, epithelial cells responding to TGFβ may play the dominant role. Here we review the growing body of literature on the emerging Mina pathway in T cells and epithelial cells and attempt to set these into a broader context. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Immunosuppressive microenvironment in neuroblastoma

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    Vito ePistoia

    2013-06-01

    Full Text Available According to the cancer immunoediting model, the interplay between tumor cells and the host immune system is crucial for the control of tumor growth. NB is a pediatric tumor that presents with metastatic disease at diagnosis in about 50% of the cases, the majority of which have poor prognosis. In this Review article, immune escape pathways adopted by human neuroblastoma (NB cells are reviewed. These include intrinsic defects of tumor cells such impaired expression of the HLA class I related antigen processing machinery and functional alterations of the tumor microenvironment induced by NB cell-derived immunosuppressive molecules as MICA and HLA-G. Finally, examples of therapeutic interventions targeting the tumor microenvironment are discussed to emphasize the concept that successful cancer treatment may be achieved using this strategy.

  12. Mouse cytokine profile skewed towards Th2 in pregnancy during ...

    African Journals Online (AJOL)

    The two classes of cytokines Th1 and Th2 determine the type of immune response elicited. The Th2 immune response is associated with successful pregnancy. Brucellosis is an intracellular bacterium that elicits the Th1 response and is known to cause spontaneous abortion in mammalian species. This study sought to ...

  13. Developmental control of integrin expression regulates Th2 effector homing

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    Integrin CD18, a component of the LFA-1 complex that also includes CD11a, is essential for Th2, but not Th1, cell homing, but the explanation for this phenomenon remains obscure. In this study, we investigate the mechanism by which Th2 effector responses require the LFA-1 complex. CD11a-deficient T ...

  14. Targeting the tumor microenvironment

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    Kenny, P.A.; Lee, G.Y.; Bissell, M.J.

    2006-11-07

    Despite some notable successes cancer remains, for the most part, a seemingly intractable problem. There is, however, a growing appreciation that targeting the tumor epithelium in isolation is not sufficient as there is an intricate mutually sustaining synergy between the tumor epithelial cells and their surrounding stroma. As the details of this dialogue emerge, new therapeutic targets have been proposed. The FDA has already approved drugs targeting microenvironmental components such as VEGF and aromatase and many more agents are in the pipeline. In this article, we describe some of the 'druggable' targets and processes within the tumor microenvironment and review the approaches being taken to disrupt these interactions.

  15. The PCa Tumor Microenvironment.

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    Sottnik, Joseph L; Zhang, Jian; Macoska, Jill A; Keller, Evan T

    2011-12-01

    The tumor microenvironment (TME) is a very complex niche that consists of multiple cell types, supportive matrix and soluble factors. Cells in the TME consist of both host cells that are present at tumor site at the onset of tumor growth and cells that are recruited in either response to tumor- or host-derived factors. PCa (PCa) thrives on crosstalk between tumor cells and the TME. Crosstalk results in an orchestrated evolution of both the tumor and microenvironment as the tumor progresses. The TME reacts to PCa-produced soluble factors as well as direct interaction with PCa cells. In return, the TME produces soluble factors, structural support and direct contact interactions that influence the establishment and progression of PCa. In this review, we focus on the host side of the equation to provide a foundation for understanding how different aspects of the TME contribute to PCa progression. We discuss immune effector cells, specialized niches, such as the vascular and bone marrow, and several key protein factors that mediate host effects on PCa. This discussion highlights the concept that the TME offers a potentially very fertile target for PCa therapy.

  16. Th1/Th2 cytokine expression in diabetic retinopathy.

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    Cao, Y L; Zhang, F Q; Hao, F Q

    2016-07-15

    Diabetic retinopathy (DR), an important complication of diabetes mellitus (DM), is not well understood. T helper cell balance (Th1/Th2) is involved in various autoimmune diseases; however, its role in DR is not understood. This study explores changes in Th1 and Th2 cytokine expression during DR. Blood samples were collected from 25 healthy volunteers (normal control group), 35 patients with type 2 DM (T2DM group) without DR, and 30 cases of T2DM patients with DR (DR group). Real-time PCR was used to measure mRNA expression of IL-2 and TNF-α, secreted from Th1 cells, and of IL-4 and IL-10, secreted from Th2 cells. We used ELISA to detect cytokine expression in serum to analyze the correlation between Th1 and Th2 cytokines. IL-2 and TNF-αmRNA and protein expression levels in the T2DM and DR groups were significantly higher than in the normal control group (P 0.05). IL-2 and TNF-αwere negatively correlated with IL-4 and IL-10 in the DR group, respectively. We found that Th1 cytokine secretion was higher and Th2 cytokines secretion was lower during DR, leading to a Th1/ Th2 imbalance, suggesting that Th1/Th2 imbalance is a side effect for DR occurrence and development.

  17. Role of a Th2 cytokine inhibitor in asthma treatment

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    Jun Tamaoki

    2004-01-01

    Full Text Available The airway wall of asthmatic patients is infiltrated with inflammatory cells, consisting chiefly of eosinophils and T lymphocytes. Among these T lymphocytes, Th2 cells are involved in the regulation of the IgE immune response and local allergic inflammation, which underlie allergic diseases. Various cytokines produced and released by Th2 cells play important roles in the development of many allergic diseases, including asthma, and the exacerbations of their disease states. Therefore, targeting of Th2 cell-derived cytokines is a rational therapeutic strategy for the treatment of asthma. Corticosteroids and immunosuppressive agents can potently inhibit Th2 cytokine-mediated responses, but have no selectivity for Th2 cells: they also exert pharmacological activity against cells other than inflammatory cells, thereby potentially causing adverse side-effects. However, suplatast tosilate is the only specific Th2 cytokine inhibitor that can be used clinically and it has been used widely in Japan as a maintenance drug in the treatment of asthma, atopic dermatitis and allergic rhinitis. There is considerable evidence of the effectiveness of suplatast tosilate in patients with mild asthma or moderate persistent asthma. Furthermore, an effect on cough variant asthma and a steroid-sparing effect have also been reported for suplatast tosilate.

  18. Tumor Biology and Microenvironment Research

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    Part of NCI's Division of Cancer Biology's research portfolio, research in this area seeks to understand the role of tumor cells and the tumor microenvironment (TME) in driving cancer initiation, progression, maintenance and recurrence.

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

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    N. L Vaquero

    2010-09-01

    . Either polars forms present a defwed citokynes secretion profile: Th1 cells (IL-2 and IFN-g dominate in tuberculoid form, whereas cytokines typically produced by Th2 cells (IL-4, IL-5 and IL-10 dominate in lepromatous form. In the first case, the macrophagic activation kills M leprae. It's lesions are located in nerves and skin only. In the second case, cell-mediated immunity is absent. The bacilli multiply uncontrolably in macrophages and infection is widely disseminated affecting other organs. Humoral immunity is exacerbated and have high levels of antibodies that cannot reach intracellular germ. The factors that determine whether the proliferation CD 4 T cells differentiate into Th1 or Th2 cell are not fully understood. Several hypothesis include genetics factors, prevail of cytokinesin the microenviroment, macrophagic disfunction; alterations in the coestimulatory molecules, on toll receptors of the innate immunity, etc. In recent years times new limphocytes subsets have been discovery (CD4+CD 25+, Tr1, Th3, Th17 that could be implicated in this desregulated immune reponses.

  20. spv locus aggravates Salmonella infection of zebrafish adult by inducing Th1/Th2 shift to Th2 polarization.

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    Wu, Shu-Yan; Wang, Li-Dan; Xu, Guang-Mei; Yang, Si-di; Deng, Qi-Feng; Li, Yuan-Yuan; Huang, Rui

    2017-08-01

    Salmonella enterica serovar typhimurium (S. typhimurium) are facultative intracellular enteric pathogens causing disease with a broad range of hosts. It was known that Th1-type cytokines such as IFN-γ, IL-12, and TNF-α etc. could induce protective immunity against intracellular pathogens, while Th2-type cytokines such as IL-4, IL-10, and IL-13 etc. are proved to help pathogens survive inside hosts and cause severe infection. One of the critical virulence factor attributes to the pathogenesis of S. typhimurium is Salmonella plasmid virulence genes (spv). Until now, the interaction between spv locus and the predictable generation of Th1 or Th2 immune responses to Salmonella has not been identified. In this study, zebrafish adults were employed to explore the effect of spv locus on Salmonella pathogenesis as well as host adaptive immune responses especially shift of Th1/Th2 balance. The pathological changes of intestines and livers in zebrafish were observed by hematoxylin-eosin (HE) staining and electron microscopy. Levels of the transcription factors of Th1 (Tbx21) and Th2 (GATA3) were measured by real-time quantitative PCR (RT-qPCR). Expression of cytokines were determined by using RT-qPCR and ELISA, respectively. Results showed that spv operon aggravates damage of zebrafish. Furthermore, it demonstrated that spv locus could inhibit the transcription of tbx21 gene and suppress the expression of cytokines IFN-γ, IL-12 and TNF-α. On the contrary, the transcription of gata3 gene could be promoted and the expression of cytokines IL-4, IL-10 and IL-13 were enhanced by spv locus. Taken together, our data revealed that spv locus could aggravate Salmonella infection of zebrafish adult by inducing an imbalance of Th1/Th2 immune response and resulting in a detrimental Th2 bias of host. Copyright © 2017. Published by Elsevier Ltd.

  1. Effect of Th1/Th2 cytokine administration on proinflammatory SKOV-3 cell activation.

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    Mielczarek-Palacz, Aleksandra; Sikora, Justyna; Kondera-Anasz, Zdzisława; Mickiewicz, Patrycja; Mickiewicz, Adam

    2016-12-01

    Interleukin(IL)-1β, IL-6 and IL-12 might associate with inflammatory processes in a tumor progression and create a specific microenvironment for tumor growth. The aim of the study was to assess whether the Th1 and Th2 type cytokines, such as IL-2 and IL-10, affect ovarian carcinoma continuous cell line (SKOV-3) pro-inflammatory activation. SKOV-3 ovarian cells and peripheral blood mononuclear cells (PBMCs) were stimulated by IL-2 and IL-10. Additionally, SKOV-3 ovarian cells and PBMCs were co-cultured together. Proinflammatory activation of cancer cells was evaluated by measurement of IL-1β and IL-6 levels in culture fluid after 72 h of incubation. SKOV-3 cells and PBMCs secreted IL-1β and IL-6. After stimulation by IL-2 and IL-10, secretion of studied parameters was changed in a dose-dependent manner. The addition of a higher IL-2 level gave rise to an increase of IL-1β, IL-6 and IL-12 secretion in SKOV-3 cells. Stimulation by IL-10 increased only IL-1β secretion in SKOV-3 cells. However, IL-6 secretion decreased after stimulation with 25 ng/ml IL-10. Activatory effects of IL-2 and inhibitory effects of IL-10 in co-culture of SKOV-3 and PBMCs were observed. Our results suggested that Th1/Th2 type of cytokines might influence pro-inflammatory activation of SKOV-3 ovarian cells. Co-cultures of SKOV-3 and PBMCs showed significant changes in cross-talk between cancer and immune cells.

  2. The intestinal microenvironment in sepsis.

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    Fay, Katherine T; Ford, Mandy L; Coopersmith, Craig M

    2017-10-01

    The gastrointestinal tract has long been hypothesized to function as "the motor" of multiple organ dysfunction syndrome. The gastrointestinal microenvironment is comprised of a single cell layer epithelia, a local immune system, and the microbiome. These three components of the intestine together play a crucial role in maintaining homeostasis during times of health. However, the gastrointestinal microenvironment is perturbed during sepsis, resulting in pathologic changes that drive both local and distant injury. In this review, we seek to characterize the relationship between the epithelium, gastrointestinal lymphocytes, and commensal bacteria during basal and pathologic conditions and how the intestinal microenvironment may be targeted for therapeutic gain in septic patients. Published by Elsevier B.V.

  3. Pathogenic memory type Th2 cells in allergic inflammation.

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    Endo, Yusuke; Hirahara, Kiyoshi; Yagi, Ryoji; Tumes, Damon J; Nakayama, Toshinori

    2014-02-01

    Immunological memory is a hallmark of adaptive immunity. Memory CD4 T helper (Th) cells are central to acquired immunity, and vaccines for infectious diseases are developed based on this concept. However, memory Th cells also play a critical role in the pathogenesis of various chronic inflammatory diseases, including asthma. We refer to these populations as 'pathogenic memory Th cells.' Here, we review recent developments highlighting the functions and characteristics of several pathogenic memory type Th2 cell subsets in allergic inflammation. Also discussed are the similarities and differences between pathogenic memory Th2 cells and recently identified type 2 innate lymphoid cells (ILC2), focusing on cytokine production and phenotypic profiles. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. The external microenvironment of healing skin wounds

    DEFF Research Database (Denmark)

    Kruse, Carla R; Nuutila, Kristo; Lee, Cameron Cy

    2015-01-01

    The skin wound microenvironment can be divided into two main components that influence healing: the external wound microenvironment, which is outside the wound surface; and the internal wound microenvironment, underneath the surface, to which the cells within the wound are exposed. Treatment...

  5. Reprogramming the Metastatic Microenvironment to Combat Disease Recurrence

    Science.gov (United States)

    2016-10-01

    dominant immunologic response7,10. Instead many patients have significant numbers of tumor-infiltrating innate immune cells including macrophages and...using existing breast cancer patient samples to create a biomarker panel that combines disseminated tumor cell (DTC) classification and “ immune ...protects tumor cells from the cytotoxic effects of chemotherapy4. This protective microenvironment may also create an immune privileged site that prevents

  6. 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...... anti-Ig did not circumvent the need for IL-5 for autonomous IL-2 responses. Consistent with the above, interaction with an IL-5-producing Th2 clone induced strong autonomous B cell responses to IL-2. Qualitative differences of Th2 help over that of Th1 may thus be attributable to their differential...

  7. Effects of glucan treatment on the Th1/Th2 balance in patients with allergic rhinitis: a double-blind placebo-controlled study.

    Science.gov (United States)

    Kirmaz, Cengiz; Bayrak, Papatya; Yilmaz, Ozge; Yuksel, Hasan

    2005-06-01

    Allergic rhinitis (AR) is a disease characterized by IgE-mediated, allergic inflammation of the nasal mucosa. T helper (Th) 2 cells play an important role in the development of IgE-mediated diseases such as AR, with local overproduction of Th2 cytokines (IL-4, IL-5 and IL-13) at the site of allergic inflammation. Th1 cytokines (IL-12 and IFN-gamma) are known to suppress this Th2 immune response, aiding the treatment of these diseases. Beta-1,3-1,6-glucan (Glucan) is an immunomodulator stimulating particularly the antitumor response. An efficient antitumor stimulation can be achieved through a Th1-mediated immune response. The aim of this study was to investigate the effects of Glucan on the immunopathogenic processes in the microenvironment to determine if it reverses the Th2-mediated immune response in AR to Th1-mediated response. 24 Olea europea mono-sensitized patients with AR were randomized into Glucan and placebo groups. The Glucan group consisted of 12 patients who received Glucan treatment for 12 weeks, while the placebo group of 12 patients received placebo during the same period. A nasal provocation test (NPT) with Olea europea was performed at the beginning and end of treatment, and nasal lavage followed the positive NPT. IL-4, IL-5, IFN-gamma and IL-12 levels and the eosinophil count (%) were measured in nasal lavage fluid (NLF) samples. Simultaneously, peripheral blood eosinophil % values were measured. After treatment, IL-4 and IL-5 levels in NLF from the Glucan group were found to have decreased significantly (p = 0.027, p = 0.04; respectively), while IL-12 levels were found to have significantly increased (p = 0.008). However, IFN-gamma levels had not changed. On the other hand, none of the cytokine levels had changed significantly in the placebo group following treatment. Moreover, the percentage of eosinophils in the NLF was found to have decreased significantly after treatment in the Glucan group (p = 0.01), while that of the placebo group did

  8. Th2 Regulation of Viral Myocarditis in Mice: Different Roles for TLR3 versus TRIF in Progression to Chronic Disease

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    Eric D. Abston

    2012-01-01

    Full Text Available Viral infections are able to induce autoimmune inflammation in the heart. Here, we investigated the role of virus-activated Toll-like receptor (TLR3 and its adaptor TRIF on the development of autoimmune coxsackievirus B3 (CVB3 myocarditis in mice. Although TLR3- or TRIF-deficient mice developed similarly worse acute CVB3 myocarditis and viral replication compared to control mice, disease was significantly worse in TRIF compared to TLR3-deficient mice. Interestingly, TLR3-deficient mice developed an interleukin (IL-4-dominant T helper (Th2 response during acute CVB3 myocarditis with elevated markers of alternative activation, while TRIF-deficient mice elevated the Th2-associated cytokine IL-33. Treatment of TLR3-deficient mice with recombinant IL-33 improved heart function indicating that elevated IL-33 in the context of a classic Th2-driven response protects against autoimmune heart disease. We show for the first time that TLR3 versus TRIF deficiency results in different Th2 responses that uniquely influence the progression to chronic myocarditis.

  9. [Immunomodulation of Uncaria tomentosa over dendritic cells, il-12 and profile TH1/TH2/TH17 in breast cancer].

    Science.gov (United States)

    Núñez, César; Lozada-Requena, Iván; Ysmodes, Tíndara; Zegarra, Daniel; Saldaña, Fatima; Aguilar, José

    2015-10-01

    Objetives. This study aimed to research the in vitro immunomodulatory effects of an Uncaria tomentosa hydroalcoholic extract standardized (5.03%, pentacyclic oxindole alkaloids) (UT-POA) on the immunophenotype of dendritic cells (DC) subsets, Th1, Th2, Th17 and IL-12 cytokines from patients with stage II breast cancer (BCII) and healthy women (H). Blood of 11 H and 7 BCII was obtained, PBMC were isolated and cultured for 2h with/without various concentrations of UT-POA and stimulated or not with LPS for 24h. PBMC were labeled with specific antibodies for DC and in the supernatant we measured Th1/Th2/Th17 cytokines, both by flow cytometry. Furthermore IL-12 was measured by ELISA. UT-POA did not alter DC or accessory molecules expression in BCII. However, H exhibited a decrease in the percentage of mDC (myeloid DC) and an increase in HLA-DR and CD86 expression at 1000 μg/mL. IL-12 secretion was modified only in the H group, increasing p70 subunit and decreasing p40 subunit. UT-POA increased Th1 (IFN-γ and IL-2), Th2 (IL-4) and Th17 (IL-17) secretion in both groups. UT-POA increased the production of cytokines related with anti-tumoral response at concentrations of 500-1000 μg/mL. This positive effect should be evaluated not only systemically but also in the tumor microenvironment in further studies. UT-POA may be a useful phytochemical in chemoprevention and in the alternative use in cancer therapies.

  10. Biomimetic microenvironments for regenerative endodontics.

    Science.gov (United States)

    Kaushik, Sagar N; Kim, Bogeun; Walma, Alexander M Cruz; Choi, Sung Chul; Wu, Hui; Mao, Jeremy J; Jun, Ho-Wook; Cheon, Kyounga

    2016-01-01

    Regenerative endodontics has been proposed to replace damaged and underdeveloped tooth structures with normal pulp-dentin tissue by providing a natural extracellular matrix (ECM) mimicking environment; stem cells, signaling molecules, and scaffolds. In addition, clinical success of the regenerative endodontic treatments can be evidenced by absence of signs and symptoms; no bony pathology, a disinfected pulp, and the maturation of root dentin in length and thickness. In spite of the various approaches of regenerative endodontics, there are several major challenges that remain to be improved: a) the endodontic root canal is a strong harbor of the endodontic bacterial biofilm and the fundamental etiologic factors of recurrent endodontic diseases, (b) tooth discolorations are caused by antibiotics and filling materials, (c) cervical root fractures are caused by endodontic medicaments, (d) pulp tissue is not vascularized nor innervated, and (e) the dentin matrix is not developed with adequate root thickness and length. Generally, current clinical protocols and recent studies have shown a limited success of the pulp-dentin tissue regeneration. Throughout the various approaches, the construction of biomimetic microenvironments of pulp-dentin tissue is a key concept of the tissue engineering based regenerative endodontics. The biomimetic microenvironments are composed of a synthetic nano-scaled polymeric fiber structure that mimics native pulp ECM and functions as a scaffold of the pulp-dentin tissue complex. They will provide a framework of the pulp ECM, can deliver selective bioactive molecules, and may recruit pluripotent stem cells from the vicinity of the pulp apex. The polymeric nanofibers are produced by methods of self-assembly, electrospinning, and phase separation. In order to be applied to biomedical use, the polymeric nanofibers require biocompatibility, stability, and biodegradability. Therefore, this review focuses on the development and application of the

  11. The tyrosine hydroxylase 2 (TH2) system in zebrafish brain and stress activation of hypothalamic cells.

    Science.gov (United States)

    Semenova, S A; Chen, Y-C; Zhao, X; Rauvala, H; Panula, P

    2014-12-01

    Two tyrosine hydroxylases (TH1 and TH2) are found in teleost fish, but no antibodies are available for TH2 protein to analyze the detailed structure of the system. We generated antibodies targeting TH2 and used them to characterize the TH2-producing cells in larval and adult zebrafish brain. The rabbit antisera reliably detected two bands corresponding to TH1 and TH2 close to 55 kDa in brain homogenates. The antisera detected neurons in brain nuclei which express th1 and th2 mRNA; knockdown of th2 expression by morpholino oligonucleotide injection abolished both the th2 mRNA signal and immunoreactivity with the rabbit antisera in TH2 cells. Double staining of samples with the rabbit antiserum made against TH2 and a monoclonal antibody which detects only TH1 allowed identification of cell groups expressing either one of the proteins. Cell groups in preoptic area, anterior, intermediate, and posterior part of the paraventricular organ contained neurons stained with the new TH2 antisera but not with the characterized monoclonal TH1 antibody. Neurons immunoreactive for TH2 and 5-HT were distinct. In situ hybridization for the mRNA of the immediate early gene c-fos combined with TH1/TH2 immunohistochemistry was used to characterize the cells of the zebrafish brain reacting to handling stress and a noxious chemical stimulus. Strong upregulation of c-fos expression was detected in hypothalamic nuclei containing TH2 cells, but few of the c-fos-expressing cells were positive for TH2, suggesting that these stressors do not directly activate a large proportion of TH2 cells.

  12. Changes of lymphocytes in spleen and liver by local irradiation to the maxilla in mice. Th1/Th2 balance

    International Nuclear Information System (INIS)

    Tamazawa, Ken; Satoh, Daigo; Yosue, Takashi

    2001-01-01

    This study was to examine changes in cell-mediated immunity by local irradiation, in particular focusing on the Th1/Th2 balance. We investigated influence due to local irradiation (10 Gy) of a portion of the maxilla in mice. The wet-weight of spleen, the percentage and the absolute numbers of the lymphocytes in spleen, wet-weight of the liver, the percentage of lymphocytes in liver were measured using a flow cytometer and values were compared with those obtained from non-irradiated animals. Furthermore, we analysed the percentage and absolute numbers of T helper 1 (Th1) cells, T cytotoxic 1 (Tc1) cells by the intracellular cytokine. The following results were obtained: Wet-weight of the spleen showed a significant decrease one and three days after irradiation. Wet-weight of the liver did not show any significant change after irradiation. In spleen, the percentage of Th1-like cells showed a significant increase one and three days after irradiation, and one of the Th2-like cells showed a significant decrease one day after irradiation. The ratio of the Th1-like cells to Th2-like cells showed an extreme increase one and three days after irradiation. The absolute numbers of the Th1-like cells and the Th2-like cells showed a significant decrease one and three days after irradiation. In liver, the percentage of the Th1-like cells showed a significant increase one and three days after irradiation, and the percentage of the Th2-like cells did not show any significant change after irradiation. The ratio of the Th1-like cells to Th2-like cells showed a significant increase one day after irradiation. In spleen, the percentage of the Th1 cells and Tc1 cells showed a significant increase one and three days after irradiation, but neither of the absolute numbers showed any significant change after irradiation. These results indicated that the characteristic changes of Th1/Th2 balance shifted to a Th1-dominant status by irradiation, and the ability from irradiation therapy to the

  13. A T Helper Cell 2 (Th2) Immune Response against Non-self Antigens Modifies the Cytokine Profile of Autoimmune T Cells and Protects against Experimental Allergic Encephalomyelitis

    Science.gov (United States)

    Falcone, Marika; Bloom, Barry R.

    1997-01-01

    Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system (CNS), and the most commonly used experimental model for multiple sclerosis. It is mediated by autoreactive T cell clones exhibiting a T helper cell (Th) 1 cytokine profile. Nonencephalitogenic T lymphocytes specific for self or exogenous antigens have been found to suppress encephalitogenic T cell responses and to protect against autoimmune disease. The mechanisms by which exogenous antigens modulate autoimmunity are not fully understood. In this study, we tested the hypothesis that a Th2-type immune response against an exogenous, nonself antigen, keyhole limpet hemocyanin (KLH), by releasing IL-4 in the microenvironment, could shift the cytokine profile of encephalitogenic T cells from an inflammatory Th1 to a protective Th2 type. SJL/J mice were preimmunized with the KLH in incomplete Freund's adjuvant to induce a population of Th2 memory cells that would be expected to release Th2 cytokines when activated by the specific antigen at the time of EAE induction. Four weeks later, mice received an encephalitogenic challenge containing guinea pig myelin in complete Freund's adjuvant with or without KLH. All KLH primed animals not receiving the exogenous antigen at the time of EAE induction developed a severe clinical disease indistinguishable from control mice not KLH primed. In contrast, animals preimmunized and challenged with the encephalitogenic inoculum containing KLH showed either no, or markedly reduced, clinical signs. Enzyme-linked immunospot analysis demonstrated that KLH-specific T cells in the primed mice were producing IL-4 characteristic of Th2 cells. In the KLH-primed and restimulated mice, the cytokine profile of the autoreactive, myelin basic protein–specific T cells was shifted from an inflammatory Th1 towards a protective Th2 type. We infer that the presence of IL-4 secreted by KLH-specific memory Th2 cells in the lymphoid system microenvironment

  14. A T helper cell 2 (Th2) immune response against non-self antigens modifies the cytokine profile of autoimmune T cells and protects against experimental allergic encephalomyelitis.

    Science.gov (United States)

    Falcone, M; Bloom, B R

    1997-03-03

    Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system (CNS), and the most commonly used experimental model for multiple sclerosis. It is mediated by autoreactive T cell clones exhibiting a T helper cell (Th) 1 cytokine profile. Nonencephalitogenic T lymphocytes specific for self or exogenous antigens have been found to suppress encephalitogenic T cell responses and to protect against autoimmune disease. The mechanisms by which exogenous antigens modulate autoimmunity are not fully understood. In this study, we tested the hypothesis that a Th2-type immune response against an exogenous, nonself antigen, keyhole limpet hemocyanin (KLH), by releasing IL-4 in the microenvironment, could shift the cytokine profile of encephalitogenic T cells from an inflammatory Th1 to a protective Th2 type. SJL/J mice were preimmunized with the KLH in incomplete Freund's adjuvant to induce a population of Th2 memory cells that would be expected to release Th2 cytokines when activated by the specific antigen at the time of EAE induction. Four weeks later, mice received an encephalitogenic challenge containing guinea pig myelin in complete Freund's adjuvant with or without KLH. All KLH primed animals not receiving the exogenous antigen at the time of EAE induction developed a severe clinical disease indistinguishable from control mice not KLH primed. In contrast, animals preimmunized and challenged with the encephalitogenic inoculum containing KLH showed either no, or markedly reduced, clinical signs. Enzyme-linked immunospot analysis demonstrated that KLH-specific T cells in the primed mice were producing IL-4 characteristic of Th2 cells. In the KLH-primed and restimulated mice, the cytokine profile of the autoreactive, myelin basic protein-specific T cells was shifted from an inflammatory Th1 towards a protective Th2 type. We infer that the presence of IL-4 secreted by KLH-specific memory Th2 cells in the lymphoid system microenvironment in

  15. Impairment of the Intrinsic Capability of Th1 Polarization in Irradiated Mice: A Close Look at the Imbalanced Th1/Th2 Response after Irradiation.

    Science.gov (United States)

    Chen, Renxiang; Wang, Yi-Wen; Fornace, Albert J; Li, Heng-Hong

    2016-12-01

    Two major CD4 + T-helper (Th) lineages are Th1 and Th2, and well balanced Th1/Th2 responses are essential for immune function. In previously published studies, it was reported that radiation induces a Th1/Th2 immune imbalance toward a Th2-dominant direction, and this imbalance may contribute to postirradiation immune dysfunction. The polarization of Th cells is driven by the cytokine milieu and controlled by intracellular regulatory pathways that respond to cytokine signaling. It is widely accepted that radiation induces cytokine aberration, however, the precise alterations of cytokines in various tissue environments have been difficult to evaluate. In addition, the effects of radiation on the intrinsic functions of Th cells remain uncharacterized. Therefore, how radiation affects Th1/Th2 balance remains somewhat unclear. To address this, we investigated the changes in the polarization capability of Th cells by isolating them from mice previously exposed to radiation and assessing the cells in an established in vitro Th polarization system. Our novel results demonstrate that prior exposure to radiation led to the persistent aberration of the inherent capability of Th cells to differentiate into Th1 and Th2 lineages. The parallel changes in expression of Th1-specific master transcription factors and the key genes in metabolic reprograming indicated that radiation affects the core components in Th1 polarization. While Th1 differentiation was impaired after irradiation, little adverse effect was observed in Th2 differentiation; both of these findings contribute to the known phenotypes of Th1/Th2 imbalance caused by radiation.

  16. Stable T-bet+GATA-3+ Th1/Th2 Hybrid Cells Arise In Vivo, Can Develop Directly from Naive Precursors, and Limit Immunopathologic Inflammation

    Science.gov (United States)

    Peine, Michael; Fröhlich, Anja; Hegazy, Ahmed N.; Kühl, Anja A.; Grevelding, Christoph G.; Höfer, Thomas; Hartmann, Susanne; Löhning, Max

    2013-01-01

    Differentiated T helper (Th) cell lineages are thought to emerge from alternative cell fate decisions. However, recent studies indicated that differentiated Th cells can adopt mixed phenotypes during secondary immunological challenges. Here we show that natural primary immune responses against parasites generate bifunctional Th1 and Th2 hybrid cells that co-express the lineage-specifying transcription factors T-bet and GATA-3 and co-produce Th1 and Th2 cytokines. The integration of Th1-promoting interferon (IFN)-γ and interleukin (IL)-12 signals together with Th2-favoring IL-4 signals commits naive Th cells directly and homogeneously to the hybrid Th1/2 phenotype. Specifically, IFN-γ signals are essential for T-bet+GATA-3+ cells to develop in vitro and in vivo by breaking the dominance of IL-4 over IL-12 signals. The hybrid Th1/2 phenotype is stably maintained in memory cells in vivo for months. It resists reprogramming into classic Th1 or Th2 cells by Th1- or Th2-promoting stimuli, which rather induce quantitative modulations of the combined Th1 and Th2 programs without abolishing either. The hybrid phenotype is associated with intermediate manifestations of both Th1 and Th2 cell properties. Consistently, hybrid Th1/2 cells support inflammatory type-1 and type-2 immune responses but cause less immunopathology than Th1 and Th2 cells, respectively. Thus, we propose the self-limitation of effector T cells based on the stable cell-intrinsic balance of two opposing differentiation programs as a novel concept of how the immune system can prevent excessive inflammation. PMID:23976880

  17. Stable T-bet(+GATA-3(+ Th1/Th2 hybrid cells arise in vivo, can develop directly from naive precursors, and limit immunopathologic inflammation.

    Directory of Open Access Journals (Sweden)

    Michael Peine

    Full Text Available Differentiated T helper (Th cell lineages are thought to emerge from alternative cell fate decisions. However, recent studies indicated that differentiated Th cells can adopt mixed phenotypes during secondary immunological challenges. Here we show that natural primary immune responses against parasites generate bifunctional Th1 and Th2 hybrid cells that co-express the lineage-specifying transcription factors T-bet and GATA-3 and co-produce Th1 and Th2 cytokines. The integration of Th1-promoting interferon (IFN-γ and interleukin (IL-12 signals together with Th2-favoring IL-4 signals commits naive Th cells directly and homogeneously to the hybrid Th1/2 phenotype. Specifically, IFN-γ signals are essential for T-bet(+GATA-3(+ cells to develop in vitro and in vivo by breaking the dominance of IL-4 over IL-12 signals. The hybrid Th1/2 phenotype is stably maintained in memory cells in vivo for months. It resists reprogramming into classic Th1 or Th2 cells by Th1- or Th2-promoting stimuli, which rather induce quantitative modulations of the combined Th1 and Th2 programs without abolishing either. The hybrid phenotype is associated with intermediate manifestations of both Th1 and Th2 cell properties. Consistently, hybrid Th1/2 cells support inflammatory type-1 and type-2 immune responses but cause less immunopathology than Th1 and Th2 cells, respectively. Thus, we propose the self-limitation of effector T cells based on the stable cell-intrinsic balance of two opposing differentiation programs as a novel concept of how the immune system can prevent excessive inflammation.

  18. Effect of the Premalignant and Tumor Microenvironment on Immune Cell Cytokine Production in Head and Neck Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, Sara D. [Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425 (United States); De Costa, Anna-Maria A. [Department of Otolaryngology, Head and Neck Surgery, Medical University of South Carolina, 135 Rutledge Avenue, Charleston, SC 29425 (United States); Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425 (United States); Young, M. Rita I., E-mail: rita.young@va.gov [Department of Otolaryngology, Head and Neck Surgery, Medical University of South Carolina, 135 Rutledge Avenue, Charleston, SC 29425 (United States); Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425 (United States); Medical Research Service (151), Ralph H. Johnson Veterans Affairs Medical Center, 109 Bee Street, Charleston, SC 29401 (United States)

    2014-04-02

    Head and neck squamous cell carcinoma (HNSCC) is marked by immunosuppression, a state in which the established tumor escapes immune attack. However, the impact of the premalignant and tumor microenvironments on immune reactivity has yet to be elucidated. The purpose of this study was to determine how soluble mediators from cells established from carcinogen-induced oral premalignant lesions and HNSCC modulate immune cell cytokine production. It was found that premalignant cells secrete significantly increased levels of G-CSF, RANTES, MCP-1, and PGE{sub 2} compared to HNSCC cells. Splenocytes incubated with premalignant supernatant secreted significantly increased levels of Th1-, Th2-, and Th17-associated cytokines compared to splenocytes incubated with HNSCC supernatant. These studies demonstrate that whereas the premalignant microenvironment elicits proinflammatory cytokine production, the tumor microenvironment is significantly less immune stimulatory and may contribute to immunosuppression in established HNSCC.

  19. Transcription Factors Oct-1 and GATA-3 Cooperatively Regulate Th2 Cytokine Gene Expression via the RHS5 within the Th2 Locus Control Region

    Science.gov (United States)

    Kim, Kiwan; Kim, Najung; Lee, Gap Ryol

    2016-01-01

    The T helper type 2 (Th2) locus control region (LCR) regulates Th2 cell differentiation. Several transcription factors bind to the LCR to modulate the expression of Th2 cytokine genes, but the molecular mechanisms behind Th2 cytokine gene regulation are incompletely understood. Here, we used database analysis and an oligonucleotide competition/electrophoretic mobility shift assays to search for transcription factors binding to RHS5, a DNase I hypersensitive site (DHS) within the Th2 LCR. Consequently, we demonstrated that GATA-binding protein-3 (GATA-3), E26 transformation-specific protein 1 (Ets-1), octamer transcription factor-1 (Oct-1), and Oct-2 selectively associate with RHS5. Furthermore, chromatin immunoprecipitation and luciferase reporter assays showed that Oct-1 and Oct-2 bound within the Il4 promoter region and the Th2 LCR, and that Oct-1 and GATA-3 or Oct-2 synergistically triggered the transactivational activity of the Il4 promoter through RHS5. These results suggest that Oct-1 and GATA-3/Oct-2 direct Th2 cytokine gene expression in a cooperative manner. PMID:26840450

  20. Optical microassembly platform for constructing reconfigurable microenvironment for biomedical studies

    DEFF Research Database (Denmark)

    Rodrigo, Peter John; Kelemen, Lóránd; Palima, Darwin

    2009-01-01

    Cellular development is highly influenced by the surrounding microenvironment. We propose user-reconfigurable microenvironments and bio-compatible scaffolds as an approach for understanding cellular development processes. We demonstrate a model platform for constructing versatile microenvironment...

  1. Competition for Antigen between Th1 and Th2 Responses Determines the Timing of the Immune Response Switch during Mycobaterium avium Subspecies paratuberulosis Infection in Ruminants

    Science.gov (United States)

    Magombedze, Gesham; Eda, Shigetoshi; Ganusov, Vitaly V.

    2014-01-01

    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 (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. PMID:24415928

  2. The Vascular Microenvironment and Systemic Sclerosis

    Directory of Open Access Journals (Sweden)

    Tracy Frech

    2010-01-01

    Full Text Available The role of the vascular microenvironment in the pathogenesis Systemic Sclerosis (SSc is appreciated clinically as Raynaud's syndrome with capillary nail bed change. This manifestation of vasculopathy is used diagnostically in both limited and diffuse cutaneous subsets of SSc, and is thought to precede fibrosis. The degree of subsequent fibrosis may also be determined by the vascular microenvironment. This paper describes why the vascular microenvironment might determine the degree of end-organ damage that occurs in SSc, with a focus on vascular cell senescence, endothelial progenitor cells (EPC including multipotential mesenchymal stem cells (MSC, pericytes, and angiogenic monocytes. An explanation of the role of EPC, pericytes, and angiogenic monocytes is important to an understanding of SSc pathogenesis. An evolving understanding of the vascular microenvironment in SSc may allow directed treatment.

  3. The thymus microenvironment in regulating thymocyte differentiation

    OpenAIRE

    Gameiro, Jacy; Nagib, Patrícia; Verinaud, Liana

    2010-01-01

    The thymus plays a crucial role in the development of T lymphocytes by providing an inductive microenvironment in which committed progenitors undergo proliferation, T-cell receptor gene rearrangements and thymocyte differentiate into mature T cells. The thymus microenvironment forms a complex network of interaction that comprises non lymphoid cells (e.g., thymic epithelial cells, TEC), cytokines, chemokines, extracellular matrix elements (ECM), matrix metalloproteinases and other soluble prot...

  4. The cAMP response element modulator (CREM) regulates T(H)2 mediated inflammation

    NARCIS (Netherlands)

    Verjans, Eva; Ohl, Kim; Reiss, Lucy K; van Wijk, Femke; Toncheva, Antonaneta A; Wiener, Anastasia; Yu, Yin; Rieg, Annette D; Gaertner, Vincent D; Roth, Johannes; Knol, Edward; Kabesch, Michael; Wagner, Norbert; Uhlig, Stefan; Martin, Christian; Tenbrock, Klaus

    2015-01-01

    A characteristic feature of allergic diseases is the appearance of a subset of CD4+ cells known as TH2 cells, which is controlled by transcriptional and epigenetic mechanisms. We aimed to analyze the role of CREM, a known transcriptional activator of T cells, with regard to TH2 responses and

  5. 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

  6. Palladium-induced Th2 cytokine responses reflect skin test reactivity

    NARCIS (Netherlands)

    Muris, J.; Feilzer, A.J.; Kleverlaan, C.J.; Rustemeyer, T.; van Hoogstraten, I.M.W.; Scheper, R.J.; von Blomberg, B.M.E.

    2012-01-01

    Recently, a crucial role of Th2 responses in nickel allergic contact dermatitis (ACD) was demonstrated. As palladium allergy is an issue of growing interest, the diagnostic potential of Th2 parameters for palladium sensitization was investigated. Palladium (Na2[PdCl4])-induced lymphocyte

  7. Molecular events by which dendritic cells promote Th2 immune protection in helmith infection.

    Science.gov (United States)

    Méndez-Samperio, Patricia

    2016-10-01

    Helminth parasites are a major cause of global infectious diseases, affecting nearly one quarter of the world's population. The common feature of helminth infections is to skew the immune system towards a T-helper 2 (Th2) response that helps to control disease. Dendritic cells (DCs), which are professional antigen-presenting cells, play a critical role for Th2 skewing against helminth parasites. However, the molecular mechanisms by which helminth antigens activate DCs for Th2 polarization have not yet been clearly defined. This review provides a focused update on the major role of DCs for inducing and/or enhancing Th2 immune responses in helminthic infection and will discuss the main signalling-dependent and independent mechanisms by which helminth antigens activate DCs for Th2 skewing.

  8. 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

    2015-06-21

    To investigate the effects of activated rat hepatic stellate cells (HSCs) on rat Th1/Th2 profile in vitro. Growth and survival of activated HSCs and CD4(+) T lymphocytes cultured alone or together was assessed after 24 or 48 h. CD4(+) T lymphocytes were then cultured with or without activated HSCs for 24 or 48 h and the proportion of Th1 [interferon (IFN)-γ(+)] and Th2 [interleukin (IL)-4(+)] cells was assessed by flow cytometry. Th1 and Th2 cell apoptosis was assessed after 24 h of co-culture using a caspase-3 staining procedure. Differentiation rates of Th1 and Th2 cells from CD4(+) T lymphocytes that were positive for CD25 but did not express IFN-γ or IL-4 were also assessed after 48 h of co-culture with activated HSCs. Galectin-9 expression in HSCs was determined by immunofluorescence and Western blotting. ELISA was performed to assess galectin-9 secretion from activated HSCs. Co-culture of CD4(+) T lymphocytes with activated rat HSCs for 48 h significantly reduced the proportion of Th1 cells compared to culture-alone conditions (-1.73% ± 0.71%; P Th1/Th2 ratio was significantly decreased (-0.44 ± 0.13; P Th1 cells was decreased (-65.71 ± 9.67; P Th1 (12.27% ± 0.99%; P Th1 cell apoptosis rate was significantly higher than in Th2 cells (P Th1 and Th2 cells; however, the increase in the proportion of Th2 cells was significantly higher than that of Th1 cells (1.85% ± 0.48%; P Th1/Th2 profile, inhibiting the Th1 response and enhancing the Th2 response, and this may be a novel pathway for liver fibrogenesis.

  9. Mixed Th2 and non-Th2 inflammatory pattern in the asthma–COPD overlap: a network approach

    Directory of Open Access Journals (Sweden)

    Pérez de Llano L

    2018-02-01

    the nature of inflammation in patients with ACO. Objectives: We aimed at investigating the role and interaction of common markers of systemic inflammation (IL-6, IL-8, and tumor necrosis factor-α, Th2-related markers (periostin, IL-5, and IL-13, and IL-17 in asthma, COPD, and ACO. Methods: This is a cross-sectional study of patients aged ≥40 years with a post-bronchodilator forced expiratory volume in the first second/forced vital capacity <0.70 recruited from outpatient clinics in tertiary hospitals with a clinical diagnosis of asthma, COPD, or ACO. ACO was defined by a history of smoking >10 pack-years in a patient with a previous diagnosis of asthma or by the presence of eosinophilia in a patient with a previous diagnosis of COPD. Clinical, functional, and inflammatory parameters were compared between categories using discriminant and network analysis. Results: In total, 109 ACO, 89 COPD, and 94 asthma patients were included. Serum levels (median [interquartile range] of IL-5 were higher in asthma patients than in COPD patients (2.09 [0.61–3.57] vs 1.11 [0.12–2.42] pg/mL, respectively; p=0.03, and IL-8 levels (median [interquartile range] were higher in COPD patients than in asthma patients (9.45 [6.61–13.12] vs 7.03 [4.69–10.44] pg/mL, respectively; p<0.001. Their values in ACO were intermediate between those in asthma and in COPD. Principal component and network analysis showed a mixed inflammatory pattern in ACO in between asthma and COPD. IL-13 was the most connected node in the network, with different weights among the three conditions. Conclusion: Asthma and COPD are two different inflammatory conditions that may overlap in some patients, leading to a mixed inflammatory pattern. IL-13 could be central to the regulation of inflammation in these conditions. Keywords: asthma mechanisms, COPD mechanisms, inflammatory cytokines, overlap, network analysis, IL-13

  10. Clinical characteristics and expression of Th1-Th2 cytokines in the cerebrospinal fluid of patients with cryptococcal meningitis

    Directory of Open Access Journals (Sweden)

    Hui BU

    2014-08-01

    (P = 0.000, for all.  Conclusions In acute phase, the Th2 response is dominant in patients with CM. However, the immune response shifts towards to Th1 response in the stable phase, providing direct evidence that the imbalance of Th1-Th2 cytokines is related to the pathogenesis of CM. doi: 10.3969/j.issn.1672-6731.2014.08.007

  11. TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology

    Science.gov (United States)

    Entwistle, Lewis J.; Khoury, Hania; Papoutsopoulou, Stamatia; Mahmood, Radma; Mansour, Nuha R.; Ching-Cheng Huang, Stanley; Pearce, Edward J.; Pedro S. de Carvalho, Luiz; Ley, Steven C.

    2016-01-01

    Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8 –/–mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8 –/–M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis. PMID:27487182

  12. Th1-, Th2-, and Th17-associated cytokine expression in hypopharyngeal carcinoma and clinical significance.

    Science.gov (United States)

    Chen, Xuemei; Wang, Junfu; Wang, Rui; Su, Qinghong; Luan, Junwen; Huang, Haiyan; Zhou, Peng; Liu, Jinsheng; Xu, Xiaoqun

    2016-02-01

    Th0 cells differentiate into Th1 or Th2 depending on multiple transcription factors acting on specific time points to regulate gene expression. Th17 cells, a subset of IL-17-producing T cells distinct from Th1 or Th2 cells, have been described as key players in inflammation and autoimmune diseases as well as cancer development. In the present study, 53 patients with hypopharyngeal cancer were included. The expression levels of Th1-, Th2- and Th17-associated cytokines in hypopharyngeal cancer tissues and pericarcinoma tissues were detected. The relationship between Th1, Th2, or Th17 infiltration and metastasis was studied. Our results showed that the mRNA and protein expressions of Th1 cytokines were lower, while the expressions of Th2 and Th17 cytokines were higher in tumor tissues, and the intensity of expression was strengthened with clinical stage increasing. Cancer tissues had higher level expressions of Th2 and Th17 cytokines than that of pericarcinoma tissues. From the above data, we speculated that high expressions of Th2- and Th17-associated cytokines in hypopharyngeal carcinoma may contribute to cancer development and metastasis.

  13. Which biomarkers are effective for identifying Th2-driven inflammation in asthma?

    Science.gov (United States)

    Diamant, Zuzana; Tufvesson, Ellen; Bjermer, Leif

    2013-10-01

    Recognition of asthma as a heterogeneous disease revealed different potential molecular targets and urged the development of targeted, customized treatment modalities. Evidence was provided for different inflammatory subsets of asthma and more recently, further refined to T helper (Th)2-high and Th2-low subphenotypes with different responsiveness to standard and targeted pharmacotherapy. Given these differences in immunology and pathophysiology, proof of concept studies of novel treatment modalities for asthma should be performed in adequate, well-defined phenotypes. In this review, we describe both existing and novel biomarkers of Th2-inflammation in asthma that can be applied to classify asthma subphenotypes in clinical studies and for treatment monitoring.

  14. 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.

  15. Susceptibility to programmed cell death in T-lymphocytes from septic patients: a mechanism for lymphopenia and Th2 predominance.

    Science.gov (United States)

    Roth, Georg; Moser, Bernhard; Krenn, Claus; Brunner, Markus; Haisjackl, Markus; Almer, Gabriele; Gerlitz, Sabine; Wolner, Ernst; Boltz-Nitulescu, George; Ankersmit, Hendrik J

    2003-09-05

    Sepsis causes lymphopenia which is inversely correlated with patient survival. The role of apoptosis-specific immune-activation and activation-induced cell-death in sepsis is incompletely understood. Fifteen septic patients and 20 healthy controls were included. T-cell proliferation was measured by [3H]thymidine uptake. Apoptosis and cell phenotype were determined by FACS. sTNFR1, sCD95, interleukin-1beta converting enzyme (sICE), and interleukin (IL)-10 were measured by ELISA. PHA and CD3-driven T-cell proliferation were significantly decreased in septic patients. The percentages of CD3(+) and CD4(+) T cells and CD19(+) B cells were significantly reduced. Percent memory T-cells (CD45RO(+)) and cells undergoing apoptosis (CD95(+)/annexin-V(+)) were significantly increased in sepsis. Moreover, sCD95, sTNFRI, and ICE were significantly increased. Anti-CD3 antibody triggering induced a 56% increase of CD4 T-cell death in septic patients vs. 7.5% in controls relative to IgG. Serum level of IL-10, a Th2 cytokine, was enhanced. These findings strongly suggest that in septic patients Th1 T-cells are selectively susceptible to undergo apoptosis. This observation provides an additional pathophysiological concept in the genesis of Th2 dominance.

  16. A Longitudinal Study of the Role of T Cell subset, Th1/Th2 cytokines ...

    African Journals Online (AJOL)

    A Longitudinal Study of the Role of T Cell subset, Th1/Th2 cytokines and antiplasmodial antibodies in uncomplicated Malaria in a Village Population Chronically Exposed to Plasmodium falciparum Malaria.

  17. Combined crystal chemistry and DFT studies of ThNCl and Th2N2X (X: chalcogen) behaving as pseudo-binaries

    Science.gov (United States)

    Matar, Samir F.; Kfoury, Charbel N.

    2018-02-01

    Common features and peculiar differentiations characterize binary and ternary thorium nitride Th3N4, thorium nitride chloride ThNCl and the family of thorium nitride chalcogenides Th2N2X (X = O, S, Se, Te) investigated in the framework of the quantum density functional theory DFT. Particularly the dominant effect of the Th-N covalent bond stronger than ionic Th-Cl/Th-X ones as identified from analyses of bonding from overlap integral, electron localization function mapping, electronic density of states and charge transfer, is found at the origin of the layered-like structural arrangements in Th-N monolayers within ThNCl (Cl / [ThN]/ Cl) and Th-N double layers in Th2N2X (X / [Th2N2] / X) with the result of pseudo binary compounds: [ThN]+Cl- and [Th2N2] 2+X2-. All compounds are found semi-conducting with ∼2 eV band gap. It is claimed that such insights into Solid State Chemistry can help rationalizing complex compounds more comprehensively (two examples given).

  18. Priming dendritic cells for Th2 polarization: lessons learned from helminths and implications for metabolic disorders

    Directory of Open Access Journals (Sweden)

    Leonie eHussaarts

    2014-10-01

    Full Text Available Nearly one quarter of the world’s population is infected with helminth parasites. A common feature of helminth infections is the manifestation of a type 2 immune response, characterized by T helper 2 (Th2 cells that mediate anti-helminth immunity. In addition, recent literature described a close association between type 2 immune responses and wound repair, suggesting that a Th2 response may concurrently mediate repair of parasite-induced damage. The molecular mechanisms that govern Th2 responses are poorly understood, although it is clear that dendritic cells (DCs, which are the most efficient antigen-presenting cells in the immune system, play a central role. Here, we review the molecular mechanisms by which DCs polarize Th2 cells, examining both helminth antigens and helminth-mediated tissue damage as Th2-inducing triggers. Finally, we discuss the implication of these findings in the context of metabolic disorders, as recent literature indicates that various aspects of the Th2-associated inflammatory response contribute to metabolic homeostasis.

  19. The cAMP response element modulator (CREM) regulates TH2 mediated inflammation

    Science.gov (United States)

    Verjans, Eva; Ohl, Kim; Reiss, Lucy K.; van Wijk, Femke; Toncheva, Antonaneta A.; Wiener, Anastasia; Yu, Yin; Rieg, Annette D.; Gaertner, Vincent D.; Roth, Johannes; Knol, Edward; Kabesch, Michael; Wagner, Norbert; Uhlig, Stefan; Martin, Christian; Tenbrock, Klaus

    2015-01-01

    A characteristic feature of allergic diseases is the appearance of a subset of CD4+ cells known as TH2 cells, which is controlled by transcriptional and epigenetic mechanisms. We aimed to analyze the role of CREM, a known transcriptional activator of T cells, with regard to TH2 responses and allergic diseases in men and mice. Here we demonstrate that T cells of asthmatic children and PBMCs of adults with atopy express lower mRNA levels of the transcription factor CREM compared to cells from healthy controls. CREM deficiency in murine T cells results in enhanced TH2 effector cytokines in vitro and in vivo and CREM−/− mice demonstrate stronger airway hyperresponsiveness in an OVA-induced asthma model. Mechanistically, both direct CREM binding to the IL-4 and IL-13 promoter as well as a decreased IL-2 dependent STAT5 activation suppress the TH2 response. Accordingly, mice selectively overexpressing CREMα in T cells display decreased TH2 type cytokines in vivo and in vitro, and are protected in an asthma model. Thus, we provide evidence that CREM is a negative regulator of the TH2 response and determines the outcome of allergic asthma. PMID:26459392

  20. Regulation of an Autoimmune Model for Multiple Sclerosis in Th2-Biased GATA3 Transgenic Mice

    Directory of Open Access Journals (Sweden)

    Viromi Fernando

    2014-01-01

    Full Text Available T helper (Th2 cells have been proposed to play a neuroprotective role in multiple sclerosis (MS. This is mainly based on “loss-of-function” studies in an animal model for MS, experimental autoimmune encephalomyelitis (EAE, using blocking antibodies against Th2 related cytokines, and knockout mice lacking Th2-related molecules. We tested whether an increase of Th2 responses (“gain-of-function” approach could alter EAE, the approach of novel GATA binding protein 3 (GATA3-transgenic (tg mice that overexpress GATA3, a transcription factor required for Th2 differentiation. In EAE induced with myelin oligodendrocyte glycoprotein (MOG35−55 peptide, GATA3-tg mice had a significantly delayed onset of disease and a less severe maximum clinical score, compared with wild-type C57BL/6 mice. Histologically, GATA3-tg mice had decreased levels of meningitis and demyelination in the spinal cord, and anti-inflammatory cytokine profiles immunologically, however both groups developed similar levels of MOG-specific lymphoproliferative responses. During the early stage, we detected higher levels of interleukin (IL-4 and IL-10, with MOG and mitogen stimulation of regional lymph node cells in GATA3-tg mice. During the late stage, only mitogen stimulation induced higher IL-4 and lower interferon-γ and IL-17 production in GATA3-tg mice. These results suggest that a preexisting bias toward a Th2 immune response may reduce the severity of inflammatory demyelinating diseases, including MS.

  1. 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.

  2. Targeting the tumor microenvironment for cancer therapy.

    Science.gov (United States)

    Sounni, Nor Eddine; Noel, Agnès

    2013-01-01

    With the emergence of the tumor microenvironment as an essential ingredient of cancer malignancy, therapies targeting the host compartment of tumors have begun to be designed and applied in the clinic. The malignant features of cancer cells cannot be manifested without an important interplay between cancer cells and their local environment. The tumor infiltrate composed of immune cells, angiogenic vascular cells, lymphatic endothelial cells, and cancer-associated fibroblastic cells contributes actively to cancer progression. The ability to change these surroundings is an important property by which tumor cells are able to acquire some of the hallmark functions necessary for tumor growth and metastatic dissemination. Thus in the clinical setting the targeting of the tumor microenvironment to encapsulate or destroy cancer cells in their local environment has become mandatory. The variety of stromal cells, the complexity of the molecular components of the tumor stroma, and the similarity with normal tissue present huge challenges for therapies targeting the tumor microenvironment. These issues and their interplay are addressed in this review. After a decade of intensive clinical trials targeting cellular components of the tumor microenvironment, more recent investigations have shed light on the important role in cancer progression played by the noncellular stromal compartment composed of the extracellular matrix. A better understanding of how the tumor environment affects cancer progression should provide new targets for the isolation and destruction of cancer cells via interference with the complex crosstalk established between cancer cells, host cells, and their surrounding extracellular matrix. © 2012 American Association for Clinical Chemistry

  3. Retnla (relmalpha/fizz1 suppresses helminth-induced Th2-type immunity.

    Directory of Open Access Journals (Sweden)

    John T Pesce

    2009-04-01

    Full Text Available Retnla (Resistin-like molecule alpha/FIZZ1 is induced during Th2 cytokine immune responses. However, the role of Retnla in Th2-type immunity is unknown. Here, using Retnla(-/- mice and three distinct helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Moreover, when chronically infected with S. mansoni cercariae, Retnla(-/- mice displayed significant increases in granulomatous inflammation in the liver and the development of fibrosis and progression to hepatosplenic disease was markedly augmented. Finally, Retnla(-/- mice infected with the gastrointestinal (GI parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla(-/- mice developed stronger Th2 responses, which could be reversed by exogenous rRelmalpha treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-gamma, while tissue localization and cell isolation experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses.

  4. Immunomodulation Mechanism of Antidepressants: Interactions between Serotonin/Norepinephrine Balance and Th1/Th2 Balance

    Science.gov (United States)

    Martino, Matteo; Rocchi, Giulio; Escelsior, Andrea; Fornaro, Michele

    2012-01-01

    Neurotransmitters and hormones regulate major immune functions, including the selection of T helper (Th)1 or Th2 cytokine responses, related to cell-mediated and humoral immunity, respectively. A role of imbalance and dynamic switching of Th1/Th2 system has been proposed, with relative displacement of the immune reserve in relation to complex interaction between Th1/Th2 and neuro-hormonal balance fluctuations, in the pathogenesis of various chronic human diseases, probably also including psychiatric disorders. Components of the stress system such as norepinephrine (NE) and glucocorticoids appear to mediate a Th2 shift, while serotonin (5-HT) and melatonin might mediate a Th1 shift. Some antidepressants would occur affecting these systems, acting on neurotransmitter balance (especially the 5-HT/NE balance) and expression levels of receptor subtypes, which in turn affect cytokine production and relative Th1/Th2 balance. It could be therefore hypothesized that the antidepressant-related increase in NE tone enhances the Th2 response, while the decrease in NE tone or the increase in 5-HT tone enhances the Th1 response. However, the neurotransmitter and Th1/Th2 balance modulation could be relative, aiming to restore physiological levels a previous imbalance in receptor sensitivity and cytokine production. The considerations on neuro-immunomodulation could represent an additional aid in the study of pathophysiology of psychiatric disorders and in the choice of specific antidepressants in specific clusters of symptoms, especially in comorbidity with internal pathologies. Furthermore limited data, reviewed here, have shown the effectiveness of some antidepressants as pure immunomodulators. However, these considerations are tentative and require experimental confirmation or refutation by future studies. PMID:23204981

  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. 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......-gamma neutralization strongly influenced the Th1/Th2 balance in BN rats, it did not affect the disease outcome. These data demonstrate that a Th1-dominated immune response is not necessarily associated with disease severity in EAMG, not only in rats with disparate MHC haplotype but also in the same rat strain......, and suggest that in a situation where complement-fixing Ab can be generated as a consequence of either Th1- or Th2-mediated T cell help, deviation of the immune response will not be an adequate strategy to prevent this Ab-mediated autoimmune disease....

  7. Foxa2 regulates leukotrienes to inhibit Th2-mediated pulmonary inflammation.

    Science.gov (United States)

    Tang, Xiaoju; Liu, Xiaojing J; Tian, Cuijie; Su, Qiaoli; Lei, Yi; Wu, Qingbo; He, Yangyan; Whitsett, Jeffrey A; Luo, Fengming

    2013-12-01

    Foxa2 is a member of the Forkhead family of nuclear transcription factors that is highly expressed in respiratory epithelial cells of the developing and mature lung. Foxa2 is required for normal airway epithelial differentiation, and its deletion causes goblet-cell metaplasia and Th2-mediated pulmonary inflammation during postnatal development. Foxa2 expression is inhibited during aeroallergen sensitization and after stimulation with Th2 cytokines, when its loss is associated with goblet-cell metaplasia. Mechanisms by which Foxa2 controls airway epithelial differentiation and Th2 immunity are incompletely known. During the first 2 weeks after birth, the loss of Foxa2 increases the production of leukotrienes (LTs) and Th2 cytokines in the lungs of Foxa2 gene-targeted mice. Foxa2 expression inhibited 15-lipoxygenase (Alox15) and increased Alox5 transcription, each encoding key lipoxygenases associated with asthma. The inhibition of the cysteinyl LT (CysLT) signaling pathway by montelukast inhibited IL-4, IL-5, eotaxin-2, and regulated upon activation normal T cell expressed and presumably secreted expression in the developing lungs of Foxa2 gene-targeted mice. Montelukast inhibited the expression of genes regulating mucus metaplasia, including Spdef, Muc5ac, Foxa3, and Arg2. Foxa2 plays a cell-autonomous role in the respiratory epithelium, and is required for the suppression of Th2 immunity and mucus metaplasia in the developing lung in a process determined in part by its regulation of the CysLT pathway.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Contribution of basophils to cutaneous immune reactions and Th2-mediated allergic responses

    Directory of Open Access Journals (Sweden)

    Atsushi eOtsuka

    2015-08-01

    Full Text Available Basophils are potent effector cells of innate immunity and also play a role in T helper 2 (Th2-mediated allergic responses. But, although their in vitro functions are well studied, their in vivo functions remain largely unknown. However, several mouse models of basophil depletion have recently been developed and used to investigate basophil functions. For example, in a croton oil-induced model of irritant contact dermatitis in conditionally basophil-depleted transgenic mice, we found that basophils rapidly infiltrate inflamed skin and subsequently induce infiltration of eosinophils. We also showed that basophils induce Th2 skewing upon epicutaneous sensitization with various haptens and peptide antigens. Intriguingly, basophils also promoted Th2 polarization upon protein antigen exposure in the presence of dendritic cells (DCs. The dermal DC subset associated with Th2 skewing was recently identified as CD301b+ DC. Such studies with basophil-deficient mouse models have significantly improved our understanding of the mechanisms involved in human immune-related diseases. In this review, we will focus on the relative contribution of basophils and DCs to Th2-mediated allergic responses.

  10. Effect of xanthohumol on Th1/Th2 balance in a breast cancer mouse model.

    Science.gov (United States)

    Zhang, Wenchao; Pan, Yanlong; Gou, Panhong; Zhou, Cheng; Ma, Lianqing; Liu, Qiming; Du, Yuping; Yang, Jinbo; Wang, Qin

    2018-01-01

    Xanthohumol (XN), a prenylflavonoid found in the hop plant, Humulus lupulus, exhibits a variety of biological activities. Numerous studies have reported that XN inhibits the growth of many types of cancer cells, but the effects of XN on tumor immunity have not yet been studied. We explored the effect of XN on Th1/Th2 balance and the underlying mechanism based on a BALB/c-4T1 breast cancer mouse model. The results showed that XN significantly slowed down tumor growth and inhibited expression of antitumor proliferation protein Ki-67 as well as breast cancer-specific marker cancer antigen 15-3 (CA15-3). Flow cytometric analysis revealed that XN enhanced the secretion of perforin, granzyme B and increased the ratio of CD8+/CD25+. ELISA analysis of cytokine results demonstrated that XN obviously upregulated Th1 cytokines, while downregulated Th2 cytokines. Th1/Th2 ratio analysis by flow cytometry illustrated that XN regulated the balance drift to Th1 polarization. Western blotting and immunohistochemistry (IHC) results manifested that XN induced expression of T-bet, a Th1-specific transcription factor. Furthermore, we found that XN significantly promoted the phosphorylation of signal transducer and activator of transcription (STAT)4. Our results demonstrated that XN promoted Th1/Th2 balance towards Th1 polarization, and STAT4 may play a positive role in the regulation of Th1/Th2 cytokines by XN.

  11. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma.

    Science.gov (United States)

    Choy, David F; Hart, Kevin M; Borthwick, Lee A; Shikotra, Aarti; Nagarkar, Deepti R; Siddiqui, Salman; Jia, Guiquan; Ohri, Chandra M; Doran, Emma; Vannella, Kevin M; Butler, Claire A; Hargadon, Beverley; Sciurba, Joshua C; Gieseck, Richard L; Thompson, Robert W; White, Sandra; Abbas, Alexander R; Jackman, Janet; Wu, Lawren C; Egen, Jackson G; Heaney, Liam G; Ramalingam, Thirumalai R; Arron, Joseph R; Wynn, Thomas A; Bradding, Peter

    2015-08-19

    Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes. Copyright © 2015, American Association for the Advancement of Science.

  12. 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.

  13. 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

  14. 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.

  15. Effect and Molecular Mechanisms of Traditional Chinese Medicine on Regulating Tumor Immunosuppressive Microenvironment

    Directory of Open Access Journals (Sweden)

    Qiujun Guo

    2015-01-01

    Full Text Available Traditional Chinese medicine (TCM is an important complementary strategy for treating cancer in China. The mechanism is related to regulating the internal environment and remodeling the tumor immunosuppressive microenvironment (TIM. Herein we illustrate how TIM is reformed and its protumor activity on promoting tumor cell proliferation, angiogenesis and lymphangiogenesis, tumor invasion, and the oncogenicity of cancer stem cells. Furthermore we summarize the effects and mechanism of TCM on regulating TIM via enhancing antitumor immune responses (e.g., regulating the expression of MHC molecules and Fas/FasL, attenuating cancerigenic ability of cancer stem cells and remolding immunosuppressive cells (e.g., reversing immune phenotypes of T lymphocytes and tumor associated macrophages, promoting dendritic cells mature, restraining myeloid derived suppressor cells function, and regulating Th1/Th2 factors. We also reveal the bidirectional and multitargeting functions of TCM on regulating TIM. Hopefully, it provides new theoretical basis for TCM clinical practice in cancer treatment and prevention.

  16. Bioinspired Hydrogels to Engineer Cancer Microenvironments.

    Science.gov (United States)

    Park, Kyung Min; Lewis, Daniel; Gerecht, Sharon

    2017-06-21

    Recent research has demonstrated that tumor microenvironments play pivotal roles in tumor development and metastasis through various physical, chemical, and biological factors, including extracellular matrix (ECM) composition, matrix remodeling, oxygen tension, pH, cytokines, and matrix stiffness. An emerging trend in cancer research involves the creation of engineered three-dimensional tumor models using bioinspired hydrogels that accurately recapitulate the native tumor microenvironment. With recent advances in materials engineering, many researchers are developing engineered tumor models, which are promising platforms for the study of cancer biology and for screening of therapeutic agents for better clinical outcomes. In this review, we discuss the development and use of polymeric hydrogel materials to engineer native tumor ECMs for cancer research, focusing on emerging technologies in cancer engineering that aim to accelerate clinical outcomes.

  17. Immune senescence: significance of the stromal microenvironment

    Science.gov (United States)

    Masters, A. R.; Haynes, L.; Su, D.‐M.

    2016-01-01

    Summary The immune system undergoes age‐associated changes known as immunosenescence, resulting in increased susceptibility to infections, cancers and autoimmunity in the aged. The basis of our understanding of immunosenescence has been derived primarily from studies examining intrinsic defects within many of the cells of the immune system. While these studies have provided insight into the mechanisms of immunosenescence, a picture is now emerging that the stromal microenvironment within lymphoid organs also contributes significantly to the age‐associated decline of immune function. These extrinsic defects appear to impact the functional activity of immune cells and may offer a potential target to recover immune activity. Indeed, rejuvenation studies which have targeted the stromal niche have restored immune function in aged successfully, highlighting the impact of the microenvironment towards the aetiology of immunosenescence. PMID:27529161

  18. Immunological Dysregulation in Multiple Myeloma Microenvironment

    Directory of Open Access Journals (Sweden)

    Alessandra Romano

    2014-01-01

    Full Text Available Multiple Myeloma (MM is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC in bone marrow (BM. Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target.

  19. Biological stoichiometry in tumor micro-environments.

    Directory of Open Access Journals (Sweden)

    Irina Kareva

    Full Text Available Tumors can be viewed as evolving ecological systems, in which heterogeneous populations of cancer cells compete with each other and somatic cells for space and nutrients within the ecosystem of the human body. According to the growth rate hypothesis (GRH, increased phosphorus availability in an ecosystem, such as the tumor micro-environment, may promote selection within the tumor for a more proliferative and thus potentially more malignant phenotype. The applicability of the GRH to tumor growth is evaluated using a mathematical model, which suggests that limiting phosphorus availability might promote intercellular competition within a tumor, and thereby delay disease progression. It is also shown that a tumor can respond differently to changes in its micro-environment depending on the initial distribution of clones within the tumor, regardless of its initial size. This suggests that composition of the tumor as a whole needs to be evaluated in order to maximize the efficacy of therapy.

  20. Epigenetic control of the tumor microenvironment

    Science.gov (United States)

    Marks, David L; Olson, Rachel LO; Fernandez-Zapico, Martin E

    2016-01-01

    Stromal cells of the tumor microenvironment have been shown to play important roles in both supporting and limiting cancer growth. The altered phenotype of tumor-associated stromal cells (fibroblasts, immune cells, endothelial cells etc.) is proposed to be mainly due to epigenetic dysregulation of gene expression; however, only limited studies have probed the roles of epigenetic mechanisms in the regulation of stromal cell function. We review recent studies demonstrating how specific epigenetic mechanisms (DNA methylation and histone post-translational modification-based gene expression regulation, and miRNA-mediated translational regulation) drive aspects of stromal cell phenotype, and discuss the implications of these findings for treatment of malignancies. We also summarize the effects of epigenetic mechanism-targeted drugs on stromal cells and discuss the consideration of the microenvironment response in attempts to use these drugs for cancer treatment. PMID:27700179

  1. Calcite Biohybrids as Microenvironment for Stem Cells

    Directory of Open Access Journals (Sweden)

    Razi Vago

    2012-04-01

    Full Text Available A new type of composite 3D biomaterial that provides extracellular cues that govern the differentiation processes of mesenchymal stem cells (MSCs has been developed. In the present study, we evaluated the chondrogenecity of a biohybrid composed of a calcium carbonate scaffold in its calcite polymorph and hyaluronic acid (HA. The source of the calcite scaffolding is an exoskeleton of a sea barnacle Tetraclita rifotincta (T. rifotincta, Pilsbry (1916. The combination of a calcium carbonate-based bioactive scaffold with a natural polymeric hydrogel is designed to mimic the organic-mineral composite of developing bone by providing a fine-tuned microenvironment. The results indicate that the calcite-HA interface creates a suitable microenvironment for the chondrogenic differentiation of MSCs, and therefore, the biohybrid may provide a tool for tissue-engineered cartilage.

  2. Radiation-induced decrease of CD8+ dendritic cells contributes to Th1/Th2 shift.

    Science.gov (United States)

    Liu, Hu; Li, Bailong; Jia, Xiaojing; Ma, Yan; Gu, Yifeng; Zhang, Pei; Wei, Qun; Cai, Jianming; Cui, Jianguo; Gao, Fu; Yang, Yanyong

    2017-05-01

    Exposure to ionizing radiation (IR) often reduce the helper T (Th) 1 like function, resulting in a Th1/Th2 imbalance, which could affect the efficacy of cancer radiotherapy. As the most potent antigen presenting cells, dendritic cells (DC) can be divided into several subsets with specialized function. However, there is no literature covering the changes of DC subsets and their roles in immune regulation in response to IR. In the present study, we were aimed to investigate the changes of DC subsets after IR and its relationship with Th1/Th2 immunity. We found a significant decrease of BDCA3+DC in the blood of patients treated with radiotherapy. CD8+DC, a mouse equivalent of human BDCA3+DC, was also found decreased in mice spleen, peripheral blood and lymph node tissues after irradiation. As CD8+DC mainly induce Th1 immunity, we tested the changes of Th1/Th2 response and found that IR caused a repression of Th1 immunity, indicating a possible role of CD8+DC in radiation-induced Th1/Th2 imbalance. We also found that a CD8+DC-inducing cytokine, Fms-like tyrosine kinase 3 ligand (FLT3 ligand), restored CD8+DC and reversed Th1/Th2 shift. And then we found that bone marrow cells from irradiated mice differentiated into less CD8+DC, which was also protected by FLT3 ligand. In conclusion, our data showed that IR induced a decrease of CD8+DC and Th1/Th2 shift, which was reversed by Flt3 ligand treatment, suggesting a novel mechanism for radiation-induced immunosuppression. Copyright © 2017. Published by Elsevier B.V.

  3. Effects of γ-rays on Th1 and Th2 immune function of mice

    International Nuclear Information System (INIS)

    Jin Wei; Cui Yufang; An Xiaoxia; Xu Han; Dong Bo; Liu Xiaolan; Luo Qingliang

    2007-01-01

    Objective: To observe the effects of 6 Gy whole body γ-irradiation on immune function of Th1 and Th2 in mouse, and to investigate the cellular and molecular mechanism of immune system injury induced by irradiation. Methods: Surface marker and intracellular cytokines of lymphocytes were stained with fluorescence-labeled monoclonal antibodies, then the changes of lymphocyte subpopulations, especially the Th1 and Th2 in mouse peripheral blood and spleen were analyzed by flow cytometry. Results: (1) 1 d after 6 Gy y- irradiation, lymphocytic subsets of CD 19 + and CD 8 + in spleen decreased apparently and the percentages of them were only 30% and 41% of control groups respectively (P 19 + and 14 d for CD 8 + respectively, however, up to 21 d post-irradiation they still did not return to control level. (2) Th1 subpopulations in mouse peripheral blood and spleen were significantly reduced at 1 d after irradiation and were only 2.6% and 7.6% of control groups (P 4 + / CD 8 + were significantly increased at 1 d post-irradiation in mouse spleen because of swift reduction of CD 8 + cells. Interestingly, either in peripheral blood or in spleen in irradiated mice, the ratio of Th1/Th2 were evidently raised because of the decrement of Th1 cells, exhibited obviously a phenomenon of predominant immune response of Th2 cells. Conclusions: It is suggested that the depression of mouse immune function induced by 6 Gy γ-irradiation might be caused by changes of CD 4 + /CD 8 + ratio, especially the imbalance of Th1/Th2 function subpopulations. It is shown that the imbalance of Th1/Th2 function subpopulations plays an important role in radiation-induced immune injury, thus providing a better insight into the molecular mechanism and new strategies for prevent and treatment measures of immune injury by irradiation. (authors)

  4. CYTOKINE PROFILE OF TH1- AND TH2-DEPENDENT VARIANTS OF CHRONIC GVHD

    Directory of Open Access Journals (Sweden)

    O. T. Kudaeva

    2012-01-01

    Full Text Available Abstract. Induction of chronic GVHD in the DBA/2→(C57Bl/6xDBA/2 F1 semi-allogeneic murine model results into development of Th1- and Th2-dependent immunopathological conditions that are characterized by different cytokine profiles. Chronic GVHD is accompanied by a sharp increase in IgE levels, thus presuming considerable IL-4 production. In recipients with Th2-dependent GvHD variant, elevated contents of serum IL-6, IL-7 and TNFα were also observed, which, along with other effects, may support polyclonal activation of B cells, thus leading to development of autoimmune pathology.

  5. Effects of laser immunotherapy on tumor microenvironment

    Science.gov (United States)

    Acquaviva, Joseph T.; Wood, Ethan W.; Hasanjee, Aamr; Chen, Wei R.; Vaughan, Melville B.

    2014-02-01

    The microenvironments of tumors are involved in a complex and reciprocal dialog with surrounding cancer cells. Any novel treatment must consider the impact of the therapy on the microenvironment. Recently, clinical trials with laser immunotherapy (LIT) have proven to effectively treat patients with late-stage, metastatic breast cancer and melanoma. LIT is the synergistic combination of phototherapy (laser irradiation) and immunological stimulation. One prominent cell type found in the tumor stroma is the fibroblast. Fibroblast cells can secrete different growth factors and extracellular matrix modifying molecules. Furthermore, fibroblast cells found in the tumor stroma often express alpha smooth muscle actin. These particular fibroblasts are coined cancer-associated fibroblast cells (CAFs). CAFs are known to facilitate the malignant progression of tumors. A collagen lattice assay with human fibroblast cells is used to elucidate the effects LIT has on the microenvironment of tumors. Changes in the contraction of the lattice, the differentiation of the fibroblast cells, as well as the proliferation of the fibroblast cells will be determined.

  6. Domination, Eternal Domination, and Clique Covering

    Directory of Open Access Journals (Sweden)

    Klostermeyer William F.

    2015-05-01

    Full Text Available Eternal and m-eternal domination are concerned with using mobile guards to protect a graph against infinite sequences of attacks at vertices. Eternal domination allows one guard to move per attack, whereas more than one guard may move per attack in the m-eternal domination model. Inequality chains consisting of the domination, eternal domination, m-eternal domination, independence, and clique covering numbers of graph are explored in this paper.

  7. 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...... lung function. In addition, an inverse correlation between IL-3 and IFN-gamma was observed. The results indicate involvement of endogenous GM-CSF, G-CSF and IL-3 in the skewed Th response in CF, and change to a Th1-dominated response might be achieved with GM-CSF treatment....

  8. The contact allergen dinitrochlorobenzene (DNCB) and respiratory allergy in the Th2-prone Brown Norway rat

    NARCIS (Netherlands)

    Kuper, C.F.; Stierum, R.H.; Boorsma, A.; Schijf, M.A.; Prinsen, M.; Bruijntjes, J.P.; Bloksma, N.; Arts, J.H.E.

    2008-01-01

    All LMW respiratory allergens known to date can also induce skin allergy in test animals. The question here was if in turn skin allergens can induce allergy in the respiratory tract. Respiratory allergy was tested in Th2-prone Brown Norway (BN) rats by dermal sensitization with the contact allergen

  9. Significant elevation of a Th2 cytokine, interleukin-10, in pelvic inflammatory disease.

    Science.gov (United States)

    Chen, Kuo-Shuen; Wang, Po-Hui; Yang, Shun-Fa; Lin, Ding-Bang; Lin, Yi-Jiun; Kuo, Dong-Yih; Lin, Long-Yau; Wu, Ming-Tsang; Lin, Chiao-Wen; Lee, Sheuan; Chou, Ming-Chih; Tsai, Hsiu-Ting; Hsieh, Yih-Shou

    2008-01-01

    We investigated the expressions and ratios of type 1 T helper cell (Th1) cytokines interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), as well as type 2 T helper cell (Th2) cytokines interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13) and interleukin-10 (IL-10) in pelvic inflammatory disease (PID) patients. The human cytokine LINCOplex multiplex bead array was used to measure the plasma levels of Th1 and Th2 cytokines in 50 healthy controls, as well as in 41 PID patients before and after routine protocol treatment. Significantly increased expressions of Th1 cytokine IFN-gamma (p=0.004), as well as Th2 cytokine IL-5 (p=0.001), and dramatically increased IL-10 (p=0.0001), but significantly decreased expression of Th1 cytokine IL-2 (p=0.029) in PID patients were found after comparison to the control group. The ratio of IFN-gamma to IL-13 showed a significant increase, but the ratios of IFN-gamma to IL-10 and IL-2 to IL-10 was significantly decreased in PID patients before treatment compared to after treatment and controls. The results indicate that the imbalance and cross-regulation between Th1 and Th2 cytokines pathways is probably contributed to the mechanism of PID.

  10. 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.

  11. 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 ...

  12. SerpinB2 is critical to Th2 immunity against enteric nematode infection

    Science.gov (United States)

    SerpinB2, a member of the serine protease inhibitor family, is expressed by macrophages and up-regulated significantly by inflammation. Recent studies implicated a role for SerpinB2 in the control of Th1 and Th2 immune responses, but the mechanisms of these effects are unknown. In the current study...

  13. Modulation of chicken macrophage effector function by Th1/Th2 cytokines

    Science.gov (United States)

    Regulation of macrophage activity by TH1/2 cytokines is important to maintain the balance of immunity to provide adequate protective immunity while avoiding excessive inflammation. IFN-gamma and IL-4 are the hallmark TH1 and TH2 cytokines, respectively. In avian species, information concerning reg...

  14. TH1 and TH2 cell polarization increases with aging and is modulated by zinc supplementation

    OpenAIRE

    2008-01-01

    TH1 and TH2 cell polarization increases with aging and is modulated by zinc supplementation correspondence: Corresponding author. Tel.: +49 241 8080208; fax: +49 241 8082613. (Rink, Lothar) (Rink, Lothar) Institute of Immunology, University Hospital, RWTH Aachen University - Aachen--> - GERMANY (Uciechowski, Peter) Institute of Immunology, University Hospital, RWTH Aachen University - Aachen--> - GERMAN...

  15. Tick saliva inhibits dendritic cell migration, maturation and function, while promoting development of Th2 responses

    Czech Academy of Sciences Publication Activity Database

    Skallová, Anna; Iezzi, G.; Ampenberger, F.; Kopf, M.; Kopecký, Jan

    2008-01-01

    Roč. 180, č. 9 (2008), s. 6186-9192 ISSN 0022-1767 R&D Projects: GA ČR GA524/05/0811; GA MŠk(CZ) LC06009 Institutional research plan: CEZ:AV0Z60220518 Keywords : dendritic cell * tick saliva * Th2 * immune responses Subject RIV: EC - Immunology Impact factor: 6.000, year: 2008

  16. Mixed and inhomogeneous expression profile of Th1/Th2 related cytokines detected by cytometric bead array in the saliva of patients with oral lichen planus.

    Science.gov (United States)

    Wei, Wei; Sun, Qianqian; Deng, Yiwen; Wang, Yufeng; Du, Guanhuan; Song, Chencheng; Li, Chenxi; Zhu, Mengxue; Chen, Guangjie; Tang, Guoyao

    2018-03-06

    The aim of this study was to measure T helper (Th) 1/Th2-related cytokine expression in saliva from patients with oral lichen planus (OLP), compared with healthy controls (HC group) and controls with recurrent aphthous ulcers (RAU group). Saliva was collected from 41 patients with OLP, 14 HCs, and 14 controls with RAU for Th1/Th2-related cytokines analysis with cytometric bead array. Disease activity in OLP was recorded by reticulation/keratosis, erythema, and ulceration scores. Interleukin (IL)-6, IL-10, interferon-γ (IFN-γ), and IFN-γ/IL-4 in saliva were significantly higher in the OLP group than in the HC group. A positive and significant correlation among IL-6, IL-10, and reticulation/keratosis, erythema, and ulceration scores in the OLP group was revealed. Significantly increased IL-4, IL-5, IL-6, IL-10, tumor necrosis factor-α and IFN-γ/IL-4 were found in the RAU group. Salivary cytokine profiles analyzed by cytometric bead array may provide a convenient research approach to OLP. Data indicated complicated Th1/Th2-related cytokine profile changes, rather than simple dominance model, in OLP. IL-10 and especially IL-6 may provide a surrogate endpoint for monitoring OLP. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

  20. Cytokines in systemic lupus erythematosus: far beyond Th1/Th2 dualism lupus: cytokine profiles.

    Science.gov (United States)

    Guimarães, Poliana Macedo; Scavuzzi, Bruna Miglioranza; Stadtlober, Nicole Perugini; Franchi Santos, Lorena Flor da Rosa; Lozovoy, Marcell Alysson Batisti; Iriyoda, Tatiana Mayumi Veiga; Costa, Neide Tomimura; Reiche, Edna Maria Vissoci; Maes, Michael; Dichi, Isaias; Simão, Andréa Name Colado

    2017-10-01

    The aims of this study were to delineate cytokine profiles of systemic lupus erythematosus (SLE), construct prediction models for diagnosis and disease activity using those profiles, and to examine the associations between TNFB Ncol polymorphism, body mass index (BMI) and vitamin D levels with cytokine levels. Two hundred SLE patients and 196 healthy controls participated in this case-control study. Plasma cytokines levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-1β, IL- 4, IL-6, IL-10, IL-12 and IL-17 were measured and cytokines profiles were computed. IL-6, IL-12, IL-17, IFN-γ and IL-10 levels were significantly higher in SLE, while IL-4 was lower in SLE. The Th1/Th2 and Th1+Th17/Th2 profiles were significantly higher in SLE than in healthy controls, whereas there were no significant differences in the proinflammatory cytokine profile (TNFα+IL-6+IL-1β). In total, 90.4% of all subjects were correctly classified using Th1+Th17 profile and IL-10 (positively associated) and IL-4 (negatively associated) as predictor variables (sensitivity=66.7% and specificity=96.9%). In all, 20.9% of the variance in the SLE Disease Activity Index was predicted by the Th1+Th17/Th2 ratio, IL-10 and BMI (all positively) and proinflammatory profile (inversely associated). B1/B1 genotype is accompanied by increased IL-17 and Th17/Th2 ratio, while B1/B2 genotype is accompanied by higher IL-4 and IFNγ values. 25-OH vitamin D was inversely associated with IFN-γ levels. SLE is accompanied by Th1, Th17 and Treg profile and lowered IL-4 production. Lowered vitamin D levels and B1/B1 genotype, but not BMI, contribute to changes in cytokines profiles. Future treatments should target Th1, Th2 and Th17 profiles rather than inflammatory cytokines.

  1. Does exposure to UV radiation induce a shift to a Th-2-like immune reaction?

    International Nuclear Information System (INIS)

    Ullrich, S.E.

    1996-01-01

    In addition to being the primary cause of skin cancer, UV radiation is immune suppressive and there appears to be a link between the ability of UV to suppress the immune response and induce skin cancer. Cytokines made by UV-irradiated keratinocytes play an essential role in activating immune suppression. In particular, we have found that keratinocyte-derived interleukin (IL)-10 is responsible for the systemic impairment of antigen presenting cell function and the UV-induced suppression of delayed-type hypersenstivity (DTH). Antigen presentation by splenic adherent cells isolated from UV-irradiated mice to T helper-1 type T (Th1) cells is suppressed, whereas antigen presentation to T helper-2 type T (Th2) cells is enhanced. The enhanced antigen presentation to Th2 cells and the impaired presentation to Th1 cells can be reversed in vivo by injecting the UV-irradiated mice with monoclonal anti-IL-10 antibody. Furthermore, immune suppression can be transferred from UV-irradiated mice to normal recipients by adoptive transfer of T cells. Injecting the recipient mice with anti-IL-4 or anti-IL-10 prevents the transfer of immune suppression, suggesting the suppressor cells are Th2 cells. In addition, injecting UV-irradiated mice with IL-12, a cytokine that has been shown to be the primary inducer of Th1 cells, and one that prevents the differentiation of Th2 cells in vivo, reverses UV-induced immune suppression. These findings support the hypothesis that UV exposure activates IL-10 secretion, which depresses the function of Th1 cells, while enhancing the activity of Th2 cells. (Author)

  2. Validation of Biomarkers of the Tumor Microenvironment

    Science.gov (United States)

    2015-10-01

    obtained by qPCR analysis of FFPE tissue taken from the prostatectomy tissue obtained on average 35.3 months prior to the clinical diagnosis of...microenvironment/stroma/validation/multigene classifier/ 3. OVERALL PROJECT SUMMARY Background. Conversion of biomarkers to qPCR assays on FFPE...biopsies samples. A s n o t e d l a s t y e a r , w e have p r e v i o u s l y developed a diagnostic (1) and p rognos t i c ( 2 ) assays f o r

  3. NK cells in the tumor microenvironment

    DEFF Research Database (Denmark)

    Larsen, Stine K; Gao, Yanhua; Basse, Per H

    2014-01-01

    The presence of natural killer (NK) cells in the tumor microenvironment correlates with outcome in a variety of cancers. However, the role of intratumoral NK cells is unclear. Preclinical studies have shown that, while NK cells efficiently kill circulating tumor cells of almost any origin......, they seem to have very little effect against the same type of tumor cells when these have extravasated. The ability to kill extravasated tumor cells is, however, is dependent of the level of activation of the NK cells, as more recent published and unpublished studies, discussed below, have demonstrated...... that interleukin-2-activated NK cells are able to attack well-established solid tumors....

  4. Sex-linked dominant

    Science.gov (United States)

    Inheritance - sex-linked dominant; Genetics - sex-linked dominant; X-linked dominant; Y-linked dominant ... can be either an autosomal chromosome or a sex chromosome. It also depends on whether the trait ...

  5. Cancer Cell Colonisation in the Bone Microenvironment

    Directory of Open Access Journals (Sweden)

    Casina Kan

    2016-10-01

    Full Text Available Bone metastases are a common complication of epithelial cancers, of which breast, prostate and lung carcinomas are the most common. The establishment of cancer cells to distant sites such as the bone microenvironment requires multiple steps. Tumour cells can acquire properties to allow epithelial-to-mesenchymal transition, extravasation and migration. Within the bone metastatic niche, disseminated tumour cells may enter a dormancy stage or proliferate to adapt and survive, interacting with bone cells such as hematopoietic stem cells, osteoblasts and osteoclasts. Cross-talk with the bone may alter tumour cell properties and, conversely, tumour cells may also acquire characteristics of the surrounding microenvironment, in a process known as osteomimicry. Alternatively, these cells may also express osteomimetic genes that allow cell survival or favour seeding to the bone marrow. The seeding of tumour cells in the bone disrupts bone-forming and bone-resorbing activities, which can lead to macrometastasis in bone. At present, bone macrometastases are incurable with only palliative treatment available. A better understanding of how these processes influence the early onset of bone metastasis may give insight into potential therapies. This review will focus on the early steps of bone colonisation, once disseminated tumour cells enter the bone marrow.

  6. Interaction microenvironment - Pantoea agglomerans limits maize yield

    Directory of Open Access Journals (Sweden)

    Daniel Ruíz Juárez

    2018-01-01

    Full Text Available Pantoea agglomerans has been reported as the cause of chlorotic streaks on maize leaves in the Central High Valleys of México (CVHM, but there are no current data of how the infection of this new pathogen in Mexico affects production and yield of the crop. To understand the development of the disease in the crop, two experiments with a split-plot design and three replications were established during spring-summer 2010 in different microenvironments: Ayapango and Temamatla. Three cultivars of maize (a tri-linear HS2 hybrid, the single-cross hybrid Triunfo and the native Cacahuacintle were evaluated with three P. agglomerans isolates. In the three maize cultivars, chlorotic streaks appeared on new leaves; at the ripening stage, the symptoms were less perceptible. The average incidence of plants with chlorotic streaks was higher in the town of Temamatla than in Ayapango, and in both microenvironments, the average degree of severity was less than 40%. Isolate A was the most virulent (P < 0.0001 on the three cultivars evaluated. These results will provide the basis for effective management of the disease under environmental conditions similar to those evaluated in this research.

  7. Domination versus disjunctive domination in graphs | Henning ...

    African Journals Online (AJOL)

    A dominating set in a graph G is a set S of vertices of G such that every vertex not in S is adjacent to a vertex of S. The domination number of G is the minimum cardinality of a dominating set of G. For a positive integer b, a set S of vertices in a graph G is a b-disjunctive dominating set in G if every vertex v not in S is adjacent ...

  8. Looking beyond the induction of Th2 responses to explain immunomodulation by helminths.

    Science.gov (United States)

    Nutman, T B

    2015-06-01

    Although helminth infections are characteristically associated with Th2-mediated responses that include the production of the prototypical cytokines IL-4, IL-5 and IL-13 by CD4(+) cells, the production of IgE, peripheral blood eosinophilia and mucus production in localized sites, these responses are largely attenuated when helminth infections become less acute. This modulation of the immune response that occurs with chronic helminth infection is often induced by molecules secreted by helminth parasites, by non-Th2 regulatory CD4(+) cells, and by nonclassical B cells, macrophages and dendritic cells. This review will focus on those parasite- and host-mediated mechanisms underlying the modulated T-cell response that occurs as the default in chronic helminth infections. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

  9. Influence of Th2 cells on hair cycle/growth after repeated cutaneous application of hapten.

    Science.gov (United States)

    Sugita, K; Nomura, T; Ikenouchi-Sugita, A; Ito, T; Nakamura, M; Miyachi, Y; Tokura, Y; Kabashima, K

    2014-03-01

    Exposure to contact allergens in order to produce allergic contact dermatitis (ACD) seems to induce hair cycle/growth, but the mechanism of this remains unclear. In the current study, we investigated this mechanism and found that repeated application of hapten induced production of interleukin (IL)-4 in lymph-node immune cells. In addition, hair growth was induced in mice after the adoptive transfer of T-helper (Th)2 cells that had been purified from mice exposed to repeated cutaneous application of hapten. These findings lead us to speculate that Th2 cells that are repeatedly hapten-sensitized are recruited to hapten-challenged skin areas, and thus stimulate the production of IL-4 in the vicinity of the hair follicles, which influences hair cycle/growth. Our results may provide fundamental insights into the mechanism of contact hypersensitivity-induced hair cycle/growth. © 2013 British Association of Dermatologists.

  10. 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.

  11. Looking beyond the induction of Th2 responses to explain immunomodulation by helminths

    OpenAIRE

    Nutman, Thomas B.

    2015-01-01

    Although helminth infections are characteristically associated with Th2-mediated responses that include the production of the prototypical cytokines IL-4, IL-5, and IL-13 by CD4+ cells, the production of IgE, peripheral blood eosinophilia and mucus production in localized sites, these responses are largely attenuated when helminth infections become less acute. This modulation of the immune response that occurs with chronic helminth infection is often induced by molecules secreted by helminth ...

  12. [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.

  13. Circulating levels of Th1 and Th2 chemokines in patients with ankylosing spondylitis.

    Science.gov (United States)

    Wang, Jianing; Zhao, Qi; Wang, Gaoya; Yang, Chunshu; Xu, Yong; Li, Yujia; Yang, Pingting

    2016-05-01

    Although chemokines are critical elements for the selective attraction and activation of various leukocyte subsets in the inflammatory process, there are few findings concerning T helper (Th) 1 or Th2 chemokines in ankylosing spondylitis (AS). This study was designed to determine whether serum levels of chemokines that are preferentially chemotactic for Th1 (IFN-gamma-inducible protein-10, IP-10/CXCL10) and Th2 (thymus and activation regulated chemokine, TARC/CCL17) and (macrophage derived chemokine, MDC/CCL22) cells were elevated and whether they correlated with the clinical features in patients with AS. Forty-two patients with axial AS and 25 healthy controls were enrolled into the study. Serum levels of chemokines (IP-10, TARC and MDC) and cytokines (IFN-γ, TNF-α and IL-4) were examined using ELISA. The disease activity was evaluated by Ankylosing Spondylitis Disease Activity Score (ASDAS). Serum levels of IgG, IgA, IgM, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured. Serum chemokine levels of IP-10, TARC and MDC were significantly higher in patients with AS than those in healthy controls. Serum cytokine levels of IFN-γ, TNF-α were also significantly increased, but the levels of IL-4 were not. Furthermore, IP-10 levels in AS patients correlated with ESP, CRP and ASDAS, while the levels of TARC and MDC did not correlate with these clinic indexes. Correlation analysis between the levels of chemokines and cytokines revealed a positive correlation between IP-10 and TNF-α. The levels of both Th1 and Th2 chemokines decreased under blockade of TNF-α. Our results suggest that both a Th1 chemoattractant IP-10 and Th2 chemoattractants, TARC and MDC, cooperatively play a role in the development of AS. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Treatment of allergic asthma: Modulation of Th2 cells and their responses

    Directory of Open Access Journals (Sweden)

    Erb Klaus J

    2011-08-01

    Full Text Available Abstract Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral, leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.

  15. Bonding at the Extreme. Detection and Characterization of Thorium Dimer, Th_2

    Science.gov (United States)

    Steimle, Timothy; Muscarella, Seth; Kokkin, Damian L.

    2015-06-01

    Due to the difficultly of working with actinides (radioactive, short lifetimes) and the number of electrons in these systems our chemical understanding either experimentally or theoretically on these systems is very limited. The electronic spectrum of thorium dimer, Th_2, is expected to be heavily congested due to the predicted twelve electronic states within an energy less then 1 eV of the calculated ^3Δ_g ground state. The chemical bond is predicted to be a quadruple bond in both the ground state and low lying ^1σ^+_g state (T_e=400 cm-1). Experimentally Th_2 was been detected in the gas phase by mass spectrometry. Here we report on the detection of the gas fluorescence spectrum of Th_2 in the 495-560 nm range via application of 2D LIF spectroscopy and attempts to record high resolution field free and Zeeman spectra. B.J. Roos, P.-Å. Malmqvist and L. Gagliardi, J. Am. Chem. Soc. 128, 17000-17006, 2006 M.C. Heaven, B.J. Barker and I.O. Antonov, J. Phys. Chem A. 118, 10867-10881, 2014

  16. A unique dermal dendritic cell subset that skews the immune response toward Th2.

    Directory of Open Access Journals (Sweden)

    Ryuichi Murakami

    Full Text Available Dendritic cell (DC subsets in the skin and draining lymph nodes (LNs are likely to elicit distinct immune response types. In skin and skin-draining LNs, a dermal DC subset expressing macrophage galactose-type C-type lectin 2 (MGL2/CD301b was found distinct from migratory Langerhans cells (LCs or CD103(+ dermal DCs (dDCs. Lower expression levels of Th1-promoting and/or cross-presentation-related molecules were suggested by the transcriptome analysis and verified by the quantitative real-time PCR analysis in MGL2(+ dDCs than in CD103(+ dDCs. Transfer of MGL2(+ dDCs but not CD103(+ dDCs from FITC-sensitized mice induced a Th2-type immune response in vivo in a model of contact hypersensitivity. Targeting MGL2(+ dDCs with a rat monoclonal antibody against MGL2 efficiently induced a humoral immune response with Th2-type properties, as determined by the antibody subclass. We propose that the properties of MGL2(+ dDCs, are complementary to those of CD103(+ dDCs and skew the immune response toward a Th2-type response.

  17. Therapeutic effect of dioscin on collagen-induced arthritis through reduction of Th1/Th2.

    Science.gov (United States)

    Guo, Yachun; Xing, Enhong; Song, Hongru; Feng, Guiying; Liang, Xiujun; An, Gao; Zhao, Xiaofei; Wang, Mi

    2016-10-01

    The aim of this study was to detect the therapeutic effect of dioscin on collagen-induced arthritis (CIA). Mice model of CIA was induced by chicken collagen II and arthritis index was assessed. After suspension of dioscin (100mg/kg/d) or triptolide was intragastrically administered, the left paw swelling and body weight of each mouse were measured. Then tissue samples were assayed by histopathological analysis. The levels of Th1 and Th2 were detected by flow cytometry. The expression of p-STAT1, p-STAT4 and p-STAT6 was demonstrated by western blot analysis, and T-bet and GATA-3 expression was detected by RT-PCR. The paw swelling and arthritis index were decreased and body weight was increased in the high dose of dioscin group compared to the model group (PTh1/Th2 in the dioscin group (0.82±0.24) and triptolide group (0.99±0.44) was lower than that in the model group (1.84±0.70, PTh1/Th2 cells, which could reduce the expression of p-STAT4, increase the expression of p-STAT6 and GATA3 in the synovial tissue. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Pulsed high-dose dexamethasone modulates Th1-/Th2-chemokine imbalance in immune thrombocytopenia.

    Science.gov (United States)

    Liu, Zongtang; Wang, Meiying; Zhou, Shufen; Ma, Ji; Shi, Yan; Peng, Jun; Hou, Ming; Guo, Chengshan

    2016-10-24

    Chemokines and chemokine receptors play important roles in autoimmune diseases; however, their role in immune thrombocytopenia (ITP) is unclear. High-dose dexamethasone (HD-DXM) may become a first-line therapy for adult patients with ITP, but the effect of HD-DXM on chemokines in ITP patients is unknown. Our aim was to investigate the mechanism of pulsed HD-DXM for management of ITP, specifically regarding the chemokine pathways. Th1-/Th2-associated chemokine and chemokine receptor profiles in ITP patients before and after pulsed HD-DXM was studied. Plasma levels of CCL5 and CXCL11 (Th1-associated) and of CCL11 (Th2-associated) were determined by ELISA. Gene expression of these three chemokines and their corresponding receptors CCR5, CXCR3, and CCR3, in peripheral blood mononuclear cells (PBMCs) was determined by quantitative RT-PCR. Thirty-three of the thirty-eight ITP patients responded effectively to HD-DXM (oral, 40 mg/day, 4 days). In ITP patients, plasma CXCL11 levels increased, while CCL11 and CCL5 decreased compared to controls (P Th1-/Th2-associated chemokines and chemokine receptors may play important roles in the pathogenesis of ITP. Importantly, regulating Th1 polarization by pulsed HD-DXM may represent a novel approach for immunoregulation in ITP.

  19. Th1/Th2 cytokine production and reception features in Graves' disease

    Directory of Open Access Journals (Sweden)

    T V Saprina

    2012-06-01

    Full Text Available Cytokines and their receptors belong to a significant role in the initiation and the subsequent course and outcome of autoimmune thyroid disease. Interleukin-2 (IL-2, interleukin-4 (IL-4 and tumor necrosis factor-alpha (TNF-α-cytokines, which have a multifaceted impact on the various stages of the immune response: the development of inflammatory response, cell proliferation, antibody and acute phase proteins synthesis. Pre-existing pattern of development of autoimmune thyroiditis (Hashimoto's thyroiditis and Graves' disease (GD as a state with two opposite positions of the predominant profile of Th1/Th2-lymphocyte activation. The study evaluated the cytokine production by Th1- and Th2-lymphocytes in patients with GD, assessment of lymphocyte receptor system and identified lymphocytes subpopulation in patients with BG, and the impact on the functional state of thyroid gland. It was shown that the immunoregulatory cytokines as Th1(IL2- and Th2(IL-4-helper lymphocytes are involved in the immune mechanism of BG. The level of IL-2, IL4, and TNF-α, and the number complementary lymphocyte receptors were not significantly changed in euthyroid or hyperthyroid GD patient. Nevertheless, there are strong correla! tions between production of immunoregulatory cytokines (IL-2, IL-4 with the functional state of the thyroid gland and increase of its volume in GD patient, what confirms the “functional synergies” of these cytokines in autoimmune inflammation in the GD.

  20. Purification and characterization of an extremely stable glucose isomerase from Geobacillus thermodenitrificans TH2.

    Science.gov (United States)

    Konak, L; Kolcuoğlu, Y; Ozbek, E; Colak, A; Ergenoglu, B

    2014-01-01

    The D-glucose/D-xylose isomerase was purified from a thermophilic bacterium, Geobacillus thermodenitrificans TH2, by precipitating with heat shock and using Q-Sepharose ion exchange column chromatography, and then characterized. The purified enzyme had a single band having molecular weight of 49 kDa on SDS-PAGE. In the presence of D-glucose as a substrate, the optimum temperature and pH of the enzyme were found to be 80 degrees C and 7.5, respectively. The purified xylose isomerase of G. thermodenitrificans TH2 was extremely stable at pH 7.5 after 96 h incubation at 4 degrees C and 50 degrees C. When the thermal stability profile was analyzed, it was determined that the purified enzyme was extremely stable during incubation periods of 4 months and 4 days at 4 degrees C and 50 degrees C, respectively. The K(m) and V(max) values of the purified xylose isomerase from G. thermodenitrificans TH2 were calculated as 32 mM and 4.68 micromol/min per mg of protein, respectively. Additionally, it was detected that some metal ions affected the enzyme activity at different ratios. The enzyme was active and stable at high temperatures and nearly neutral pHs which are desirable for the usage in the food and ethanol industry.

  1. 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.

  2. Regulatory Effect of Catalpol on Th1/Th2 cells in Mice with Bone Loss Induced by Estrogen Deficiency.

    Science.gov (United States)

    Lai, Nannan; Zhang, Jianhai; Ma, Xingyan; Wang, Bin; Miao, Xiuming; Wang, Zhaoxia; Guo, Yuqi; Wang, Li; Yao, Chengfang; Li, Xia; Jiang, Guosheng

    2015-12-01

    Estradiol (E2 ) deficiency can cause bone loss and the skew of Th1/Th2 cells. However, the correlation between the Th1/Th2 cells and the bone loss induced by estrogen deficiency remains unclear. Our aim was to investigate the role of Th1/Th2 in bone loss induced by estrogen deficiency and elucidated the therapeutical effect of catalpol in this condition. Young, sham-operated (Sham), ovariectomized (Ovx), and naturally aged mice, treated with catalpol at different doses or control vehicle, were used in this study as indicated in each experiment. ELISA assay, dual-energy X-ray absorptiometry, and flow cytometry were used to analyze E2 , C-terminal telopeptides of type I collagen (CTx-I), bone mineral density (BMD), and Th1/Th2 subsets, respectively. The mRNA and protein expressions of specific transcription factors for Th1/Th2 cells (T-bet and GATA-3) were analyzed using real-time quantitative PCR and Western blot, respectively. Bone mineral density and E2 levels positively correlated with the proportion of Th2 subset while negatively correlated with that of Th1 subset and the ratio of Th1/Th2. Catalpol alleviated bone loss effectively by regulating Th1/Th2 polarization. Catalpol promoted the expression of Th2-specific transcription factors while inhibited that associated with Th1. Th1/Th2 skew is involved in bone loss induced by estrogen deficiency. Catalpol alleviates bone loss effectively by regulating Th1/Th2 paradigm. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Down-regulation of Notch signaling pathway reverses the Th1/Th2 imbalance in tuberculosis patients.

    Science.gov (United States)

    Li, Qifeng; Zhang, Hui; Yu, Liang; Wu, Chao; Luo, Xinhui; Sun, He; Ding, Jianbing

    2018-01-01

    Th1/Th2 imbalance to Th2 is of significance in the peripheral immune responses in Tuberculosis (TB) development. However, the mechanisms for Th1/Th2 imbalance are still not well determined. Notch signaling pathway is involved in the peripheral T cell activation and effector cell differentiation. However, whether it affects Th1/Th2 imbalance in TB patients is still not known. Here, we used γ-secretase inhibitor (DAPT) to treat the peripheral blood mononuclear cells (PBMCs) from healthy people or individuals with latent or active TB infection in vitro, respectively. Then, the Th1/Th2 ratios were determined by flow cytometry, and cytokines of IFN-γ, IL-4, IL-10 in the culture supernatant were measured by CBA method. The Notch signal pathway associated proteins Hes1, GATA3 and T-bet were quantitated by real-time PCR or immunoblotting. Our results showed that DAPT effectively inhibited the protein level of Hes1. In TB patients, the Th2 ratio increased in the PBMCs, alone with the high expression of GATA3 and IL-4, resulting in the high ratios of Th2/Th1 and GATA3/T-bet in TB patients. However, Th2 cells ratio decreased after blocking the Notch signaling pathway by DAPT and the Th2/Th1 ratio in TB patients were DAPT dose-dependent, accompanied by the decrease of IL-4 and GATA3. But, its influence on Th1 ratio and Th1 related T-bet and IFN-γ levels were not significant. In conclusion, our results suggest that blocking Notch signaling by DAPT could inhibit Th2 responses and restore Th1/Th2 imbalance in TB patients. Copyright © 2017. Published by Elsevier B.V.

  4. Increased B Cell ADAM10 in Allergic Patients and Th2 Prone Mice.

    Directory of Open Access Journals (Sweden)

    Lauren Folgosa Cooley

    Full Text Available ADAM10, as the sheddase of the low affinity IgE receptor (CD23, promotes IgE production and thus is a unique target for attenuating allergic disease. Herein, we describe that B cell levels of ADAM10, specifically, are increased in allergic patients and Th2 prone WT mouse strains (Balb/c and A/J. While T cell help augments ADAM10 expression, Balb WT B cells exhibit increased ADAM10 in the naïve state and even more dramatically increased ADAM10 after anti-CD40/IL4 stimulation compared C57 (Th1 prone WT B cells. Furthermore, ADAM17 and TNF are reduced in allergic patients and Th2 prone mouse strains (Balb/c and A/J compared to Th1 prone controls. To further understand this regulation, ADAM17 and TNF were studied in C57Bl/6 and Balb/c mice deficient in ADAM10. C57-ADAM10B-/- were more adept at increasing ADAM17 levels and thus TNF cleavage resulting in excess follicular TNF levels and abnormal secondary lymphoid tissue architecture not noted in Balb-ADAM10B-/-. Moreover, the level of B cell ADAM10 as well as Th context is critical for determining IgE production potential. Using a murine house dust mite airway hypersensitivity model, we describe that high B cell ADAM10 level in a Th2 context (Balb/c WT is optimal for disease induction including bronchoconstriction, goblet cell metaplasia, mucus, inflammatory cellular infiltration, and IgE production. Balb/c mice deficient in B cell ADAM10 have attenuated lung and airway symptoms compared to Balb WT and are actually most similar to C57 WT (Th1 prone. C57-ADAM10B-/- have even further reduced symptomology. Taken together, it is critical to consider both innate B cell levels of ADAM10 and ADAM17 as well as Th context when determining host susceptibility to allergic disease. High B cell ADAM10 and low ADAM17 levels would help diagnostically in predicting Th2 disease susceptibility; and, we provide support for the use ADAM10 inhibitors in treating Th2 disease.

  5. Resistance of activated human T(h)2 cells to NO-induced apoptosis is mediated by gamma-glutamyltranspeptidase

    NARCIS (Netherlands)

    Roozendaal, R; Vellenga, E; de Jong, MA; Traanberg, KF; Postma, DS; de Monchy, JGR; Kauffman, HF

    Activation-induced death of inflammatory cells (AICD) has an important function in immune maintenance, Type 1 T-h cells are known to be more susceptible to AICD than T(h)2 cells. In the current study we examined whether NO-induced apoptosis also preferentially eliminates T(h)1 cells over Th2 cells.

  6. Interleukin 4 promotes the development of ex-Foxp3 Th2 cells during immunity to intestinal helminths

    Science.gov (United States)

    Coomes, Stephanie M.; Kannan, Yashaswini; Entwistle, Lewis J.; Perez-Lloret, Jimena; Czieso, Stephanie

    2017-01-01

    Immunity to intestinal helminth infections requires the rapid activation of T helper 2 cells (Th2 cells). However, simultaneous expansion of CD4+Foxp3+ regulatory T cells (T reg cells) impedes protective responses, resulting in chronic infections. The ratio between T reg and effector T cells can therefore determine the outcome of infection. The redifferentiation of T reg cells into Th cells has been identified in hyperinflammatory diseases. In this study, we asked whether ex–T reg Th2 cells develop and contribute to type-2 immunity. Using multigene reporter and fate-reporter systems, we demonstrate that a significant proportion of Th2 cells derive from Foxp3+ cells after Heligmosomoides polygyrus infection and airway allergy. Ex-Foxp3 Th2 cells exhibit characteristic Th2 effector functions and provide immunity to H. polygyrus. Through selective deletion of Il4ra on Foxp3+ cells, we further demonstrate IL-4 is required for the development of ex-Foxp3 Th2 cells. Collectively, our findings indicate that converting T reg cells into Th2 cells could concomitantly enhance Th2 cells and limit T reg cell–mediated suppression. PMID:28507062

  7. Association between Th1/Th2 immune imbalance and obesity in women with or without polycystic ovary syndrome.

    Science.gov (United States)

    Gong, Ping; Shi, Bingwei; Wang, Juan; Cao, Peixia; Diao, Zhenyu; Wang, Yuji; Hu, Yali; Li, Shuping

    2018-02-15

    This study aimed to investigate the Th1/Th2 cells in peripheral blood of PCOS patients, and assess the potential correlation between Th1/Th2 imbalance and obesity. Thirty-nine PCOS patients and 23 age-matched controls were enrolled. The PBMCs were obtained before pharmacological intervention in women with or without PCOS. The profiles of Th1 (IFN-γ) and Th2 (IL-4) cytokines of CD3 + CD - T lymphocyte subsets were analyzed by flow cytometry. Plasma sex hormones including E 2 , T, FSH, LH, and FINS, FPG were measured, together with BMI, WC, LH/FSH, E 2 /T and HOMA-IR index being calculated. Association between Th1/Th2 imbalance and BMI, WC were evaluated. The proportion of Th1 cells and Th1/Th2 ratio were significantly higher in PCOS patients than those in controls, accompanied by elevated T, LH, LH/FSH, FINS, HOMA-IR index and reduced E 2 /T. The Th1/Th2 ratio was increased when BMI and WC were enhanced in PCOS. Moreover, the significant difference of Th1/Th2 ratio was observed between WC subgroups of PCOS. It is concluded that Th1 type immunity is predominant in systemic immunization of PCOS patients. Th1/Th2 immune imbalance is connected with obesity, especially abdominal obesity, and may be one of the underlying mechanism for the pathogenesis of PCOS.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Immune-suppressive properties of the tumor microenvironment

    DEFF Research Database (Denmark)

    Becker, Jürgen C; Andersen, Mads Hald; Schrama, David

    2013-01-01

    Solid tumors are more than an accumulation of cancer cells. Indeed, cancerous cells create a permissive microenvironment by exploiting non-transformed host cells. Thus, solid tumors rather resemble abnormal organs composed of the cancerous cells itself and the stroma providing the supportive......-modulating capacities of the tumor microenvironment....

  10. Mitochondrial Transfer in the Leukemia Microenvironment.

    Science.gov (United States)

    Griessinger, Emmanuel; Moschoi, Ruxanda; Biondani, Giulia; Peyron, Jean-François

    2017-12-01

    The bone marrow microenvironment (BMME) is a complex ecosystem that instructs and protects hematopoietic stem cells (HSCs) and their malignant counterparts, the leukemia-initiating cells (LICs). Within the physical and functional crosstalk that takes place between HSCs, LICs, and the BMME, the transfer of organelles and of mitochondria in particular is an important new intercellular communication mode in addition to adhesion molecules, tunneling nanotubes (TNTs), and the paracrine secretion of cytokines, (onco)metabolites, and extracellular vesicles (EVs). In this review we discuss the functional roles of mitochondrial transfer between BMME and leukemic cells, and give insights into this new mechanism of drug resistance whose understanding will open the way to innovative anticancer adjuvant treatments. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Of Microenvironments and Mammary Stem Cells

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    LaBarge, Mark A; Petersen, Ole W; Bissell, Mina J

    2007-06-01

    In most adult tissues there reside pools of stem and progenitor cells inside specialized microenvironments referred to as niches. The niche protects the stem cells from inappropriate expansion and directs their critical functions. Thus guided, stem cells are able to maintain tissue homeostasis throughout the ebb and flow of metabolic and physical demands encountered over a lifetime. Indeed, a pool of stem cells maintains mammary gland structure throughout development, and responds to the physiological demands associated with pregnancy. This review discusses how stem cells were identified in both human and mouse mammary glands; each requiring different techniques that were determined by differing biological needs and ethical constraints. These studies together create a robust portrait of mammary gland biology and identify the location of the stem cell niche, elucidate a developmental hierarchy, and suggest how the niche might be manipulated for therapeutic benefit.

  12. Kinetics of TH2 biomarkers in sputum of asthmatics following inhaled allergen.

    Science.gov (United States)

    Zuiker, Rob G J A; Ruddy, Marcella K; Morelli, Nicoletta; Mogg, Robin; Rivas, Veronica M; van Dyck, Kristien; De Lepeleire, Inge; Tanen, Michael R L; Boot, J Diderik; Kamerling, Ingrid M C; Diamant, Zuzana

    2015-01-01

    Allergen-induced late airway response offers important pharmacodynamic targets, including T helper 2 (TH2) biomarkers. However, detection of inflammatory markers has been limited in dithiothreitol-processed sputum. To test whether allergen-induced TH2 inflammatory markers can be reproducibly quantified by sensitive detection techniques in ultracentrifuged sputum and the effect of fluticasone (FP) on these endpoints. Thirteen allergic asthmatics with dual allergen-induced airway responses, documented during a single-blind placebo run-in period, participated in a double-blind, two-period crossover study. Each period consisted of three consecutive days, separated by ≥3 weeks. Following randomization, subjects inhaled FP (500 µg bid, five doses total) or placebo. On Day 2 in each study period, allergen challenge was performed and airway response measured by forced expiratory volume in 1 sec (FEV1) until 7 h post-challenge. Sputum was induced 24 h pre-allergen and 7 and 24 h post-allergen. Sputum samples were split into two portions: TH2 biomarkers were quantified by Meso Scale multiplex platform following ultracentrifugation, and cell differentials were counted on Giemsa-May-Grünwald-stained cytospins. Allergen-induced changes in inflammatory endpoints were compared between FP and placebo using a mixed model ANCOVA. Inhaled allergen induced dual airway responses in all subjects during both placebo periods with reproducible late asthmatic response (LAR) and increased sputum inflammatory biomarkers (IL-2, IL-4, IL-13, and eotaxin-1) and eosinophil counts. FP effectively blunted both the LAR and the inflammatory biomarkers. Combining novel, sensitive quantification methods with ultracentrifugation allows reproducible quantification of sputum biomarkers following allergen challenge, reversed by FP. This approach allows non-invasive identification of pharmacodynamic targets for anti-asthma therapies.

  13. Neuropeptide Y induces potent migration of human immature dendritic cells and promotes a Th2 polarization.

    Science.gov (United States)

    Buttari, Brigitta; Profumo, Elisabetta; Domenici, Giacomo; Tagliani, Angela; Ippoliti, Flora; Bonini, Sergio; Businaro, Rita; Elenkov, Ilia; Riganò, Rachele

    2014-07-01

    Neuropeptide Y (NPY), a major autonomic nervous system and stress mediator, is emerging as an important regulator of inflammation, implicated in autoimmunity, asthma, atherosclerosis, and cancer. Yet the role of NPY in regulating phenotype and functions of dendritic cells (DCs), the professional antigen-presenting cells, remains undefined. Here we investigated whether NPY could induce DCs to migrate, mature, and polarize naive T lymphocytes. We found that NPY induced a dose-dependent migration of human monocyte-derived immature DCs through the engagement of NPY Y1 receptor and the activation of ERK and p38 mitogen-activated protein kinases. NPY promoted DC adhesion to endothelial cells and transendothelial migration. It failed to induce phenotypic DC maturation, whereas it conferred a T helper 2 (Th2) polarizing profile to DCs through the up-regulation of interleukin (IL)-6 and IL-10 production. Thus, during an immune/inflammatory response NPY may exert proinflammatory effects through the recruitment of immature DCs, but it may exert antiinflammatory effects by promoting a Th2 polarization. Locally, at inflammatory sites, cell recruitment could be amplified in conditions of intense acute, chronic, or cold stress. Thus, altered or amplified signaling through the NPY-NPY-Y1 receptor-DC axis may have implications for the development of inflammatory conditions.-Buttari, B., Profumo, E., Domenici, G., Tagliani, A., Ippoliti, F., Bonini, S., Businaro, R., Elenkov, I., Riganò, R. Neuropeptide Y induces potent migration of human immature dendritic cells and promotes a Th2 polarization. © FASEB.

  14. House dust extracts have both TH2 adjuvant and tolerogenic activities.

    Science.gov (United States)

    Ng, Nicholas; Lam, Diane; Paulus, Petra; Batzer, Glenda; Horner, Anthony A

    2006-05-01

    Although mechanisms remain a subject of controversy, there is general agreement that living environments influence allergic risk during the first years of life. We reasoned that sterile house dust extracts (HDEs) would have immunologic activities reflective of their environments of origin and therefore would be useful surrogates for investigations of how ambient exposures influence immune homeostasis. These experiments determined how airway HDE exposures influence adaptive responses to a coadministered antigen and subsequent airway hypersensitivity responses to antigen challenge. Mice received intranasal ovalbumin (OVA) vaccinations on a weekly basis. Select groups of mice also received intranasal HDE weekly with OVA; daily at one seventh the weekly dose, beginning 7 days before the first OVA sensitization; or both. Weekly intranasal vaccinations with OVA and HDE primed mice for the development of T(H)2-biased immune and airway hypersensitivity responses. In contrast, daily low-dose intranasal HDE exposures protected against the immunologic and pathologic outcomes associated with weekly intranasal OVA/HDE vaccinations. The T(H)2 adjuvant activities of HDEs were found to be dependant on MyD88, a molecule critical for signaling through a majority of Toll-like receptors. Moreover, the tolerogenic activity associated with daily intranasal HDE exposures could be replicated with LPS. These investigations demonstrate that in addition to allergens, living environments contain immunomodulatory materials with both T(H)2 adjuvant and tolerogenic activities. As the contents of HDEs are ubiquitous, these experiments might recapitulate and help explain clinically relevant immunologic events involved in the maintenance of aeroallergen tolerance and the dysregulated responses that lead to allergic respiratory diseases.

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

    Directory of Open Access Journals (Sweden)

    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

  16. IL-25 Promotes Th2 Immunity Responses in Asthmatic Mice via Nuocytes Activation.

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    Chao Wang

    Full Text Available Interleukin-25 (IL-25 is a potent activator of type-2 immune responses, and is responsible for airway inflammation in asthma. Previous reports have shown that IL-25 expressed hyper-reactivity in an experimental mouse-model of asthma. In addition, the production of IL-13/IL-5 promoted by nuocytes induced airway inflammation. Thus, it has been questioned whether blocking IL-25 against its receptor IL-17BR could inhibit the expression of IL-13 and IL-5 via nuocytes, and further protect against inflammation in ovalbumin (OVA induced mouse-model of asthma.In this study, in order to investigate the correlation among IL-25, IL-5, IL-13 and nuocyte activities, we used OVA-sensitization and -challenging to induce the mouse model of asthma. The murine asthmatic model was validated by histology. The expressions of IL-5, IL-13 and IL-25 were detected by ELISA, quantitative real-time PCR, and western blotting of the lung tissue. Nuocyte activation was identified by the levels of ICOS (clone C398.4A and T1/ST2 (cloneDJ8 (acting as nuocytes surface markers in the bronchoalveolar lavage fluid (BALF. This, in turn, was done by means of flow cytometry. The expressions of IL-25, IL-5 and IL-13 in our murine model were detected in the BALF.The mice sensitized and challenged with OVA showed a high expression of IL-25 in both the mRNA and protein levels in lungs. The expressions of ICOS and T1/ST2 in BALF were increased. A significant correlation between IL-25 mRNA, protein, and other Th2-cell producing cytokines (such as IL-5 and IL-13 moreover were identified. Furthermore, when the asthmatic mice were treated with anti-IL-25, both the inflammatory cells' infiltration and the inflammatory cytokines' secretion were significantly decreased. The present findings indicate that IL-25 might be involved in a series of asthmatic immune responses, playing an important role in the increase of nuocytes, and that its activation is necessary in maintaining Th2 central memory and

  17. IL-4-producing ILC2s are required for the differentiation of TH2 cells following Heligmosomoides polygyrus infection

    Science.gov (United States)

    Pelly, VS; Kannan, Y; Coomes, SM; Entwistle, LJ; Rückerl, D; Seddon, B; MacDonald, AS; McKenzie, A; Wilson, MS

    2017-01-01

    Immunity to many human and murine gastrointestinal helminth parasites requires interleukin-4 (IL-4)-directed type 2 helper (TH2) differentiation of CD4+ T cells to elicit type-2 immunity. Despite a good understanding of the inflammatory cascade elicited following helminth infection, the initial source of IL-4 is unclear. Previous studies using the rat helminth parasite Nippostronglyus brasiliensis, identified an important role for basophil-derived IL-4 for TH2 differentiation. However, basophils are redundant for TH2 differentiation following infection with the natural helminth parasite of mice Heligmosomoides polygyrus, indicating that other sources of IL-4 are required. In this study using H. polygyrus, which is controlled by IL-4-dependent immunity, we identified that group-2 innate lymphoid cells (ILC2s) produced significant amounts of IL-4 and IL-2 following H. polygyrus infection. Leukotriene D4 was sufficient to stimulate IL-4 secretion by ILC2s, and the supernatant from activated ILC2s could potently drive TH2 differentiation in vitro in an IL-4-dependent manner. Furthermore, specific deletion of IL-4 from ILC2s compromised TH2 differentiation in vivo. Overall, this study highlights a previously unrecognized and important role for ILC2-derived IL-4 for TH2 differentiation in a natural TH2-dependent model of human helminthiasis. PMID:26883724

  18. The Metalloporphyrin Antioxidant, MnTE-2-PyP, Inhibits Th2 Cell Immune Responses in an Asthma Model

    Directory of Open Access Journals (Sweden)

    Paiboon Jungsuwadee

    2012-08-01

    Full Text Available MnTE-2-PyP, a superoxide dismutase mimetic, inhibited OVA-induced airway inflammation in mice suggesting an effect on Th2 responsiveness. Thus, we hypothesized that MnTE-2-PyP may alter dendritic cell-Th2 interactions. Bone marrow derived dendritic cells (DC and OVA323-339-specific Th2 cells were cultured separately in the presence or absence of MnTE-2-PyP for 3 days prior to the co-culturing of the two cell types in the presence of an OVA323-339 peptide and in some cases stimulated with CD3/CD28. MnTE-2-PyP-pretreated DC inhibited IL-4, IL-5 and IFNγ production and inhibited Th2 cell proliferation in the DC-Th2 co-culturing system in the presence of the OVA323-339 peptide. Similar results were obtained using the CD3/CD28 cell-activation system; the addition of MnTE-2-PyP inhibited Th2 cell proliferation. MnTE-2-PyP suppressed CD25 expression on OVA-specific Th2 cells, which implied that MnTE-2-PyP can inhibit the activation of Th2 cells. MnTE-2-PyP also down-regulated co-stimulatory molecules: CD40, CD80 and CD86 on immature DC. Our studies suggest that the major mechanism by which MnTE-2-PyP inhibits airway inflammation is by acting on the DC and suppressing Th2 cell proliferation and activation.

  19. GITR signaling potentiates airway hyperresponsiveness by enhancing Th2 cell activity in a mouse model of asthma

    Directory of Open Access Journals (Sweden)

    Van Oosterhout Antoon JM

    2009-10-01

    Full Text Available Abstract Background Allergic asthma is characterized by airway hyperresponsiveness (AHR and allergic inflammation of the airways, driven by allergen-specific Th2 cells. The asthma phenotypes and especially AHR are sensitive to the presence and activity of regulatory T (Treg cells in the lung. Glucocorticoid-induced tumor necrosis factor receptor (GITR is known to have a co-stimulatory function on effector CD4+ T cells, rendering these cells insensitive to Treg suppression. However, the effects of GITR signaling on polarized Th1 and Th2 cell effector functions are not well-established. We sought to evaluate the effect of GITR signaling on fully differentiated Th1 and Th2 cells and to determine the effects of GITR activation at the time of allergen provocation on AHR and airway inflammation in a Th2-driven mouse model of asthma. Methods CD4+CD25- cells were polarized in vitro into Th1 and Th2 effector cells, and re-stimulated in the presence of GITR agonistic antibodies to assess the effect on IFNγ and IL-4 production. To evaluate the effects of GITR stimulation on AHR and allergic inflammation in a mouse asthma model, BALB/c mice were sensitized to OVA followed by airway challenges in the presence or absence of GITR agonist antibodies. Results GITR engagement potentiated cytokine release from CD3/CD28-stimulated Th2 but not Th1 cells in vitro. In the mouse asthma model, GITR triggering at the time of challenge induced enhanced airway hyperresponsiveness, serum IgE and ex vivo Th2 cytokine release, but did not increase BAL eosinophilia. Conclusion GITR exerts a differential effect on cytokine release of fully differentiated Th1 and Th2 cells in vitro, potentiating Th2 but not Th1 cytokine production. This effect on Th2 effector functions was also observed in vivo in our mouse model of asthma, resulting in enhanced AHR, serum IgE responses and Th2 cytokine production. This is the first report showing the effects of GITR activation on cytokine

  20. Th1/Th2 paradigm extended: Macrophage polarization as an unappreciated pathogen-driven escape mechanism?

    Directory of Open Access Journals (Sweden)

    Eric eMuraille

    2014-11-01

    Full Text Available The classical view of the Th1/Th2 paradigm posits that the pathogen nature, infectious cycle and persistence represent key parameters controlling the choice of effector mechanisms operating during an immune response. Thus, efficient Th1 responses are triggered by replicating intracellular pathogens, while Th2 responses would control helminth infection and promote tissue repair during the resolution phase of an infectious event. However, this vision does not account for a growing body of data describing how pathogens exploit the polarization of the host immune response to their own benefit. Recently, the study of macrophages has illustrated a novel aspect of this arm race between pathogens and the immune system, and the central role of macrophages in homeostasis, repair and defense of all tissues is now fully appreciated. Like T lymphocytes, macrophages differentiate into distinct effectors including classically (M1 and alternatively (M2 activated macrophages. Interestingly in addition to represent immune effectors, M1/M2 cells have been shown to represent potential reservoir cells to a wide range of intracellular pathogens. Subversion of macrophage cell metabolism by microbes appears as a recently uncovered immune escape strategy. Upon infection, several microbial agents have been shown to activate host metabolic pathways leading to the production of nutrients necessary to their long term persistence in host. The purpose of this review is to summarize and discuss the strategies employed by pathogens to manipulate macrophage differentiation, and in particular their basic cell metabolism, to favor their own growth while avoiding immune control.

  1. Uncaria tomentosa aqueous-ethanol extract triggers an immunomodulation toward a Th2 cytokine profile.

    Science.gov (United States)

    Domingues, Alexandre; Sartori, Alexandrina; Valente, Ligia Maria Marino; Golim, Marjorie Assis; Siani, Antonio Carlos; Viero, Rosa Marlene

    2011-08-01

    Uncaria tomentosa (Willd.) DC (Rubiaceae) is a large woody vine that is native to the Amazon and Central American rainforests and is used widely in traditional medicine for its immunomodulatory and antiinflammatory activities. The present work used in vivo immunotoxic and in vitro immunomodulatory experiments to investigate the effects of a pentacyclic oxindole alkaloid extract from U. tomentosa bark on lymphocyte phenotype, Th1/Th2 cytokine production, cellular proliferation and cytotoxicity. For the in vivo immunotoxicity testing, BALB/c male mice were treated once a day with 125, 500 or 1250 mg/kg of U. tomentosa extract for 28 days. For the in vitro protocol, lymphocytes were cultured with 10-500 μg/mg of the extract for 48 h. The extract increased the cellularity of splenic white pulp and the thymic medulla and increased the number of T helper lymphocytes and B lymphocytes. Also, a large stimulatory effect on lymphocyte viability was observed. However, mitogen-induced T lymphocyte proliferation was significantly inhibited at higher concentrations of U. tomentosa extract. Furthermore, an immunological polarization toward a Th2 cytokine profile was observed. These results suggest that the U. tomentosa aqueous-ethanol extract was not immunotoxic to mice and was able to modulate distinct patterns of the immune system in a dose-dependent manner. Copyright © 2011 John Wiley & Sons, Ltd.

  2. VOC source identification from personal and residential indoor, outdoor and workplace microenvironment samples in EXPOLIS-Helsinki, Finland

    Energy Technology Data Exchange (ETDEWEB)

    Edwards, Rufus D. [KTL-Finnish National Inst. of Public Health, Dept. of Environmental Hygiene, Kuopio (Finland); California Univ., School of Public Health, Berkeley, CA (United States); Jurvelin, J. [KTL-Finnish National Inst. of Public Health, Dept. of Environmental Hygiene, Kuopio (Finland); Jyvaeskylae Polytechnic, School of Engineering and Technology, Jyvaeskylae (Finland); Koistinen, K. [KTL-Finnish National Inst. of Public Health, Dept. of Environmental Hygiene, Kuopio (Finland); Saarela, K. [VTT, Chemical Technology, Espoo (Finland); Jantunen, M. [EC JRC, Inst. of the Environment, Ispra (Italy)

    2001-07-01

    Principal component analyses (varimax rotation) were used to identify common sources of 30 target volatile organic compounds (VOCs) in residential outdoor, residential indoor and workplace microenvironment and personal 48-h exposure samples, as a component of the EXPOLIS-Helsinki study. Variability in VOC concentrations in residential outdoor microenvironments was dominated by compounds associated with long-range transport of pollutants, followed by traffic emissions, emissions from trees and product emissions. Variability in VOC concentrations in environmental tobacco smoke (ETS) free residential indoor environments was dominated by compounds associated with indoor cleaning products, followed by compounds associated with traffic emissions, long-range transport of pollutants and product emissions. Median indoor/outdoor ratios for compounds typically associated with traffic emissions and long-range transport of pollutants exceeded 1, in some cases quite considerably, indicating substantial indoor source contributions. Changes in the median indoor/outdoor ratios during different seasons reflected different seasonal ventilation patterns as increased ventilation led to dilution of those VOC compounds in the indoor environment that had indoor sources. Variability in workplace VOC concentrations was dominated by compounds associated with traffic emissions followed by product emissions, long-range transport and air fresheners. Variability in VOC concentrations in ETS free personal exposure samples was dominated by compounds associated with traffic emissions, followed by long-range transport, cleaning products and product emissions. VOC sources in personal exposure samples reflected the times spent in different microenvironments, and personal exposure samples were not adequately represented by any one microenvironment, demonstrating the need for personal exposure sampling. (Author)

  3. Extracellular vesicles in the hematopoietic microenvironment

    Science.gov (United States)

    Butler, John T.; Abdelhamed, Sherif; Kurre, Peter

    2018-01-01

    Self-renewal and differentiation are defining characteristics of hematopoietic stem and progenitor cells, and their balanced regulation is central to lifelong function of both blood and immune systems. In addition to cell-intrinsic programs, hematopoietic stem and progenitor cell fate decisions are subject to extrinsic cues from within the bone marrow microenvironment and systemically. Yet, many of the paracrine and endocrine mediators that shape hematopoietic function remain to be discovered. Extracellular vesicles serve as evolutionarily conserved, constitutive regulators of cell and tissue homeostasis, with several recent reports supporting a role for extracellular vesicles in the regulation of hematopoiesis. We review the physiological and pathophysiological effects that extracellular vesicles have on bone marrow compartmental function while highlighting progress in understanding vesicle biogenesis, cargo incorporation, differential uptake, and downstream effects of vesicle internalization. This review also touches on the role of extracellular vesicles in hematopoietic stem and progenitor cell fate regulation and recent advances in therapeutic and diagnostic applications of extracellular vesicles in hematologic disorders. PMID:29439185

  4. Isolate domination in graphs

    Directory of Open Access Journals (Sweden)

    I. Sahul Hamid

    2016-07-01

    Full Text Available A set D of vertices of a graph G is called a dominating set of G if every vertex in V(G−D is adjacent to a vertex in D. A dominating set S such that the subgraph 〈S〉 induced by S has at least one isolated vertex is called an isolate dominating set. An isolate dominating set none of whose proper subset is an isolate dominating set is a minimal isolate dominating set. The minimum and maximum cardinality of a minimal isolate dominating set are called the isolate domination number γ0 and the upper isolate domination number Γ0 respectively. In this paper we initiate a study on these parameters.

  5. ST2 Requires Th2-, but Not Th17-, Type Airway Inflammation in Epicutaneously Antigen-Sensitized Mice

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    Hideaki Morita

    2012-01-01

    Conclusions: The IL-33/ST2 pathway is crucial for Th2-cytokine-mediated eosinophilic, rather than Th17-cytokine-mediated neutrophilic, airway inflammation in mice that had been epicutaneously sensitized with antigens and then challenged with antigen.

  6. Dry Eye Management: Targeting the Ocular Surface Microenvironment.

    Science.gov (United States)

    Zhang, Xiaobo; M, Vimalin Jeyalatha; Qu, Yangluowa; He, Xin; Ou, Shangkun; Bu, Jinghua; Jia, Changkai; Wang, Junqi; Wu, Han; Liu, Zuguo; Li, Wei

    2017-06-29

    Dry eye can damage the ocular surface and result in mild corneal epithelial defect to blinding corneal pannus formation and squamous metaplasia. Significant progress in the treatment of dry eye has been made in the last two decades; progressing from lubricating and hydrating the ocular surface with artificial tear to stimulating tear secretion; anti-inflammation and immune regulation. With the increase in knowledge regarding the pathophysiology of dry eye, we propose in this review the concept of ocular surface microenvironment. Various components of the microenvironment contribute to the homeostasis of ocular surface. Compromise in one or more components can result in homeostasis disruption of ocular surface leading to dry eye disease. Complete evaluation of the microenvironment component changes in dry eye patients will not only lead to appropriate diagnosis, but also guide in timely and effective clinical management. Successful treatment of dry eye should be aimed to restore the homeostasis of the ocular surface microenvironment.

  7. Microenvironment Tracker (MicroTrac) Model helps track air quality

    Science.gov (United States)

    MicroTrac is a model that uses global positioning system (GPS) data to estimate time of day and duration that people spend in different microenvironments (e.g., indoors and outdoors at home, work, school).

  8. Immune Priming of the Tumor Microenvironment by Radiation.

    Science.gov (United States)

    Jiang, Wen; Chan, Charles K; Weissman, Irving L; Kim, Betty Y S; Hahn, Stephen M

    2016-11-01

    Ionizing irradiation can induce a multitude of alterations within the tumor microenvironment. Unlike targeted therapies, radiation delivered to the tumor bed can prompt phenotypic changes in both normal stromal and cancer cells, leading to molecular and physiological alterations within the tumor microenvironment. These environmental modulations directly influence the degree of immunogenicity of the tumor microenvironment and may ultimately affect tumor responsiveness to cancer immunotherapies. Here we review the preclinical evidence for tumor microenvironment-mediated immune suppression and how radiation can modulate immune properties within a tumor. We then discuss the therapeutic opportunities for combining radiation with molecular agents to enhance tumor immunogenicity and how this represents a potential exciting strategy to complement immunotherapies including immune checkpoint blockers in cancer treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Microenvironment-Centred Dynamics in Aggressive B-Cell Lymphomas

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    Matilde Cacciatore

    2012-01-01

    Full Text Available Aggressive B-cell lymphomas share high proliferative and invasive attitudes and dismal prognosis despite heterogeneous biological features. In the interchained sequence of events leading to cancer progression, neoplastic clone-intrinsic molecular events play a major role. Nevertheless, microenvironment-related cues have progressively come into focus as true determinants for this process. The cancer-associated microenvironment is a complex network of nonneoplastic immune and stromal cells embedded in extracellular components, giving rise to a multifarious crosstalk with neoplastic cells towards the induction of a supportive milieu. The immunological and stromal microenvironments have been classically regarded as essential partners of indolent lymphomas, while considered mainly negligible in the setting of aggressive B-cell lymphomas that, by their nature, are less reliant on external stimuli. By this paper we try to delineate the cardinal microenvironment-centred dynamics exerting an influence over lymphoid clone progression in aggressive B-cell lymphomas.

  10. A glutamic acid decarboxylase 65-specific Th2 cell clone immunoregulates autoimmune diabetes in nonobese diabetic mice.

    Science.gov (United States)

    Tisch, R; Wang, B; Atkinson, M A; Serreze, D V; Friedline, R

    2001-06-01

    Several studies have provided indirect evidence in support of a role for beta cell-specific Th2 cells in regulating insulin-dependent diabetes (IDDM). Whether a homogeneous population of Th2 cells having a defined beta cell Ag specificity can prevent or suppress autoimmune diabetes is still unclear. In fact, recent studies have demonstrated that beta cell-specific Th2 cell clones can induce IDDM. In this study we have established Th cell clones specific for glutamic acid decarboxylase 65 (GAD65), a known beta cell autoantigen, from young unimmunized nonobese diabetic (NOD) mice. Adoptive transfer of a GAD65-specific Th2 cell clone (characterized by the secretion of IL-4, IL-5, and IL-10, but not IFN-gamma or TGF-beta) into 2- or 12-wk-old NOD female recipients prevented the progression of insulitis and subsequent development of overt IDDM. This prevention was marked by the establishment of a Th2-like cytokine profile in response to a panel of beta cell autoantigens in cultures established from the spleen and pancreatic lymph nodes of recipient mice. The immunoregulatory function of a given Th cell clone was dependent on the relative levels of IFN-gamma vs IL-4 and IL-10 secreted. These results provide direct evidence that beta cell-specific Th2 cells can indeed prevent and suppress autoimmune diabetes in NOD mice.

  11. A role for interleukin-33 in T(H)2-polarized intestinal inflammation?

    DEFF Research Database (Denmark)

    Seidelin, J B; Rogler, G; Nielsen, O H

    2011-01-01

    Interleukin 33 (IL-33) is a recently discovered cytokine member of the IL-1 superfamily that is widely expressed in fixed tissue cells, including endothelial and epithelial cells. IL-33 induces helper T cells, mast cells, eosinophils, and basophils to produce type-2 cytokines through binding...... to the ST2/IL-1 receptor accessory protein complex. Recent studies have shown IL-33 to be upregulated in intestinal parasite infection and in epithelial cells and myofibroblasts in ulcerative colitis (UC). The findings point to a role for IL-33 in directing the T(H)2-type immune responses in these types...... of mucosal inflammation. As the IL-33/ST2 receptor axis can be manipulated by various blocking antibodies, this could be a potential therapeutic target in the future treatment of UC....

  12. The bone marrow microenvironment - Home of the leukemic blasts.

    Science.gov (United States)

    Shafat, Manar S; Gnaneswaran, Bruno; Bowles, Kristian M; Rushworth, Stuart A

    2017-09-01

    Acute Myeloid Leukaemia (AML) is a genetically, biologically and clinically heterogeneous set of diseases, which are characterised by an increased growth of abnormal myeloid progenitor cells within the bone marrow (BM). Ex-vivo AML exhibits a high level of spontaneous apoptosis. Furthermore, relapse for patients achieving remission occurs from minimal residual disease harboured within the BM microenvironment. Taken together, these observations illustrate the importance of the BM microenvironment in sustaining AML. While significant progress has been made elaborating the small-scale genetic mutations and larger-scale chromosomal translocations that contribute to the development of AML and its prognosis in response to treatment, less is understood about the complex microenvironment of the BM, which is known to be a key player in the pathogenesis of the disease. As we look towards future therapies, the consideration that the BM microenvironment is uniquely important as a niche for AML - coupled with the idea that leukaemic blasts are more likely to be genetically unstable and therefore evolve resistance to conventional chemotherapies - make the functions of the non-malignant cells of the BM attractive targets for therapy. In this review, we discuss the microanatomy of the BM and provide an overview of the evidence supporting the role of the BM microenvironment in creating conditions conducive to the survival and proliferation of AML blasts. Ultimately, we examine the therapeutic potential of uncoupling AML from the BM microenvironment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Polarization of TH2 response is decreased during pregnancy in systemic lupus erythematosus.

    Science.gov (United States)

    Iaccarino, L; Ghirardello, A; Zen, M; Villalta, D; Tincani, A; Punzi, L; Doria, A

    2012-12-11

    This study evaluated some cytokines involved in the Th1-Th2 shift during pregnancy in patients with systemic lupus erythematosus (SLE) and healthy women. Twenty-seven consecutive successful pregnancies in 26 SLE patients and 28 pregnancies in 28 matched healthy subjects, as controls, were enrolled and prospectively studied. Sera obtained at first and third trimesters of pregnancy were tested for IL-1α, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, INF-γ, and TNF-α with a highly sensitive, multiplexed sandwich ELISA (SearchLight Human Inflammatory Cytokine Array). Statistics were performed by SPSS package. IL-8 serum levels were higher in the first (P<0.0001) and third (P=0.003) trimesters of pregnancy in SLE patients compared with controls, INF-γ serum levels in the third trimester (P=0.009), and IL-10 serum levels in the first and third trimesters (P=0.055 and P<0.0001, respectively). IL-2 (r=0.524 P=0.010), IL-12 (r=0.549 P=0.007), IFN-γ (r=0.492 P=0.017), and IL-6 (r=0.515 P=0.020) serum levels correlated with disease activity in SLE patients in the first trimester of pregnancy. Cytokine profile was similar in patients with and without lupus nephritis both in the first and in the third trimesters of pregnancy. IL-8 serum levels were lower in patients with a previous diagnosis of antiphospholipid antibody syndrome compared with those without, both in the first and in the third trimesters of pregnancy. In SLE patients, a lower than expected decrease in Th1 cytokine serum levels was observed in the third trimester of gestation which could contribute to a lower Th2 cytokine polarization during pregnancy.

  14. Triclosan Induces Thymic Stromal Lymphopoietin in Skin Promoting Th2 Allergic Responses.

    Science.gov (United States)

    Marshall, Nikki B; Lukomska, Ewa; Long, Carrie M; Kashon, Michael L; Sharpnack, Douglas D; Nayak, Ajay P; Anderson, Katie L; Jean Meade, B; Anderson, Stacey E

    2015-09-01

    Triclosan is an antimicrobial chemical incorporated into many personal, medical and household products. Approximately, 75% of the U.S. population has detectable levels of triclosan in their urine, and although it is not typically considered a contact sensitizer, recent studies have begun to link triclosan exposure with augmented allergic disease. We examined the effects of dermal triclosan exposure on the skin and lymph nodes of mice and in a human skin model to identify mechanisms for augmenting allergic responses. Triclosan (0%-3%) was applied topically at 24-h intervals to the ear pinnae of OVA-sensitized BALB/c mice. Skin and draining lymph nodes were evaluated for cellular responses and cytokine expression over time. The effects of triclosan (0%-0.75%) on cytokine expression in a human skin tissue model were also examined. Exposure to triclosan increased the expression of TSLP, IL-1β, and TNF-α in the skin with concomitant decreases in IL-25, IL-33, and IL-1α. Similar changes in TSLP, IL1B, and IL33 expression occurred in human skin. Topical application of triclosan also increased draining lymph node cellularity consisting of activated CD86(+)GL-7(+) B cells, CD80(+)CD86(+) dendritic cells, GATA-3(+)OX-40(+)IL-4(+)IL-13(+) Th2 cells and IL-17 A(+) CD4 T cells. In vivo antibody blockade of TSLP reduced skin irritation, IL-1β expression, lymph node cellularity, and Th2 responses augmented by triclosan. Repeated dermal exposure to triclosan induces TSLP expression in skin tissue as a potential mechanism for augmenting allergic responses. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.

  15. Th1/Th2 cytokines in Type 1 diabetes: Relation to duration of disease and gender

    Directory of Open Access Journals (Sweden)

    Hajar Vaseghi

    2016-01-01

    Full Text Available Background: T-cells are important in the pathogenesis of Type 1 diabetes (T1D. However, the exact role of T-cell subpopulations in this pathway remains unknown. The purpose of this study was to assess the expression pattern of T helper 1 (Th1 interferon-gamma (IFN-γ and Th2 interleukin-4 (IL-4 cytokines and their relationship with sex and disease duration in T1D patients. Materials and Methods: This study was conducted on 21 T1D patients and 22 healthy subjects. Gene expression analysis of peripheral blood mononuclear cells (PBMCs was performed using real-time reverse transcriptase polymerase chain reaction. Results: IFN-γ gene expression was significantly lower in T1D patients compared with controls (P 0.05 while IL-4 mRNA expression in male patients was about 1.9 folds higher than female patients. Moreover, IFN-γ mRNA expression in female patients was about 1.8 folds lower than male patients. Patients were divided into two groups regarding their disease duration: 10 years. A significant increase in the IL-4 expression was observed between two groups of patients compared to controls (P < 0.0001. Conversely, there was a significant difference in the expression of IFN-γ only between patients with more than 10 years of disease duration (P = 0.02. Conclusion: These data propose supplementary implications for the role of Th1/Th2 imbalance in T1D immunopathogenesis. Moreover, factors such as sex and disease duration may have some influence on cytokine mRNA expression.

  16. 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.

  17. Cigarette smoke enhances Th-2 driven airway inflammation and delays inhalational tolerance

    Directory of Open Access Journals (Sweden)

    Joos Guy F

    2008-05-01

    Full Text Available Abstract Background Active smoking increases asthma severity and is related to diminished treatment efficacy. Animal models in which inhalation of both allergen and mainstream cigarette smoke are combined can help us to understand the complex interaction between both agents. We have recently shown that, in allergic mice, the airway inflammation can be cleared by repeated allergen challenge, resulting in the establishment of a state of inhalational tolerance. Methods In this study, we assessed in vivo the impact of cigarette smoke on the efficacy and time course of this form of tolerance induction. We exposed sensitized mice to concurrent mainstream cigarette smoke and allergen (Ovalbumin- OVA and measured the airway inflammation at different time points. Results We first confirmed that aerosolized OVA administered for a prolonged time period (4–8 weeks resulted in the establishment of tolerance. Concurrent OVA and smoke exposure for 2 weeks showed that tobacco smoke enhanced the Th-2 driven airway inflammation in the acute phase. In addition, the induction of the tolerance by repeated inhalational OVA challenge was delayed significantly by the tobacco smoke, since 4 weeks of concurrent exposure resulted in a more persistent eosinophilic airway inflammation, paralleled by a more mature dendritic cell phenotype. However, smoke exposure could not prevent the establishment of tolerance after 8 weeks of antigen exposure as shown by both histopathology (disappearance of the Th-2 driven inflammation and by in vivo functional experiments. In these tolerized mice, some of the inflammatory responses to the smoke were even attenuated. Conclusion Cigarette smoke enhances acute allergic inflammation and delays, but does not abrogate the development of tolerance due to prolonged challenge with inhaled antigen in experimental asthma.

  18. Topics on domination

    CERN Document Server

    Hedetniemi, ST

    1991-01-01

    The contributions in this volume are divided into three sections: theoretical, new models and algorithmic. The first section focuses on properties of the standard domination number &ggr;(G), the second section is concerned with new variations on the domination theme, and the third is primarily concerned with finding classes of graphs for which the domination number (and several other domination-related parameters) can be computed in polynomial time.

  19. Total well dominated trees

    DEFF Research Database (Denmark)

    Finbow, Arthur; Frendrup, Allan; Vestergaard, Preben D.

    cardinality then G is a total well dominated graph. In this paper we study composition and decomposition of total well dominated trees. By a reversible process we prove that any total well dominated tree can both be reduced to and constructed from a family of three small trees....

  20. Dominating Sets and Domination Polynomials of Paths

    Directory of Open Access Journals (Sweden)

    Saeid Alikhani

    2009-01-01

    Full Text Available Let G=(V,E be a simple graph. A set S⊆V is a dominating set of G, if every vertex in V\\S is adjacent to at least one vertex in S. Let 𝒫ni be the family of all dominating sets of a path Pn with cardinality i, and let d(Pn,j=|𝒫nj|. In this paper, we construct 𝒫ni, and obtain a recursive formula for d(Pn,i. Using this recursive formula, we consider the polynomial D(Pn,x=∑i=⌈n/3⌉nd(Pn,ixi, which we call domination polynomial of paths and obtain some properties of this polynomial.

  1. Global regulator SATB1 recruits beta-catenin and regulates T(H2 differentiation in Wnt-dependent manner.

    Directory of Open Access Journals (Sweden)

    Dimple Notani

    2010-01-01

    Full Text Available In vertebrates, the conserved Wnt signalling cascade promotes the stabilization and nuclear accumulation of beta-catenin, which then associates with the lymphoid enhancer factor/T cell factor proteins (LEF/TCFs to activate target genes. Wnt/beta -catenin signalling is essential for T cell development and differentiation. Here we show that special AT-rich binding protein 1 (SATB1, the T lineage-enriched chromatin organizer and global regulator, interacts with beta-catenin and recruits it to SATB1's genomic binding sites. Gene expression profiling revealed that the genes repressed by SATB1 are upregulated upon Wnt signalling. Competition between SATB1 and TCF affects the transcription of TCF-regulated genes upon beta-catenin signalling. GATA-3 is a T helper type 2 (T(H2 specific transcription factor that regulates production of T(H2 cytokines and functions as T(H2 lineage determinant. SATB1 positively regulated GATA-3 and siRNA-mediated knockdown of SATB1 downregulated GATA-3 expression in differentiating human CD4(+ T cells, suggesting that SATB1 influences T(H2 lineage commitment by reprogramming gene expression. In the presence of Dickkopf 1 (Dkk1, an inhibitor of Wnt signalling, GATA-3 is downregulated and the expression of signature T(H2 cytokines such as IL-4, IL-10, and IL-13 is reduced, indicating that Wnt signalling is essential for T(H2 differentiation. Knockdown of beta-catenin also produced similar results, confirming the role of Wnt/beta-catenin signalling in T(H2 differentiation. Furthermore, chromatin immunoprecipitation analysis revealed that SATB1 recruits beta-catenin and p300 acetyltransferase on GATA-3 promoter in differentiating T(H2 cells in a Wnt-dependent manner. SATB1 coordinates T(H2 lineage commitment by reprogramming gene expression. The SATB1:beta-catenin complex activates a number of SATB1 regulated genes, and hence this study has potential to find novel Wnt responsive genes. These results demonstrate that SATB1 orchestrates T(H2 lineage commitment by mediating Wnt/beta-catenin signalling. This report identifies a new global transcription factor involved in beta-catenin signalling that may play a major role in dictating the functional outcomes of this signalling pathway during development, differentiation, and tumorigenesis.

  2. Polarization of ILC2s in Peripheral Blood Might Contribute to Immunosuppressive Microenvironment in Patients with Gastric Cancer

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    Qingli Bie

    2014-01-01

    Full Text Available Newly identified nuocytes or group 2 innate lymphoid cells (ILC2s play an important role in Th2 cell mediated immunity such as protective immune responses to helminth parasites, allergic asthma, and chronic rhinosinusitis. However, the contributions of ILC2s in the occurrence and development of cancer remain unknown. Our previous study found that there was a predominant Th2 phenotype in patients with gastric cancer. In this study, the ILC2s related genes or molecules in PBMC from patients with gastric cancer were measured, and the potential correlation between them was analyzed. The expression levels of RORα, GATA3, T1/ST2, IL-17RB, CRTH2, IL-33, IL-5, and IL-4 mRNA were significantly increased in patients, but no significant changes were found in ICOS, CD45, and IL-13 expression, and there was a positive correlation between RORα or IL-13 and other related factors, such as ICOS and CD45. The increased frequency of ILC2s was also found in PBMC of patients by flow cytometry. In addition, the mRNA of Arg1 and iNOS were also significantly increased in patients. These results suggested that there are polarized ILC2s in gastric cancer patients which might contribute to immunosuppressive microenvironment and closely related to the upregulation of MDSCs and M2 macrophages.

  3. Broad Th2 neutralization and anti-inflammatory action of pentosan polysulfate sodium in experimental allergic rhinitis.

    Science.gov (United States)

    Sanden, Caroline; Mori, Michiko; Jogdand, Prajakta; Jönsson, Jimmie; Krishnan, Ravi; Wang, Xiangdong; Erjefält, Jonas S

    2017-09-01

    Th2 cytokines like interleukin-4, -5, and -13 are regarded as important drivers of the immunopathology underlying allergic rhinitis (AR) and asthma. The present study explores the capacity of pentosan polysulfate sodium (PPS), a semi-synthetic heparin-like macromolecular carbohydrate, to bind Th2 cytokines and exert biological neutralization in vitro, as well as anti-inflammatory actions in vivo. The capacity of PPS to bind recombinant Th2 cytokines was tested with surface plasmon resonance (SPR) technology and biological Th2 neutralization was assessed by Th2-dependent proliferation assays. The in vivo anti-inflammatory action of PPS was studied using a validated Guinea-pig model of AR. Binding studies revealed a strong and specific binding of PPS to IL-4, IL-5, and IL-13 with IC values suggesting as stronger cytokine binding than for heparin. Cytokine binding translated to a biological neutralization as PPS dose dependently inhibited Th2-dependent cell proliferation. Topical administration of PPS 30 min prior to nasal allergen challenge of sensitized animals significantly reduced late phase plasma extravasation, luminal influx of eosinophils, neutrophils, and total lavage leukocytes. Similar, albeit not statistically secured, effects were found for tissue leukocytes and mucus hyper-secretion. The anti-inflammatory effects of PPS compared favorably with established topical nasal steroid treatment. This study points out PPS as a potent Th2 cytokine-binding molecule with biological neutralization capacity and broad anti-inflammatory effects in vivo. As such PPS fulfills the role as a potential candidate molecule for the treatment of AR and further studies of clinical efficacy seems highly warranted. © 2017 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd.

  4. MicroRNA-145 influences the balance of Th1/Th2 via regulating RUNX3 in asthma patients.

    Science.gov (United States)

    Fan, Linxia; Wang, Xiaojun; Fan, Linlan; Chen, Qizhang; Zhang, Hong; Pan, Hui; Xu, Aixia; Wang, Hongjuan; Yu, Yang

    To delineate the underlying mechanism of microRNA-145 modulate the balance of Th1/Th2 via targeting RUNX3 in asthma patients. Peripheral blood samples were collected from asthma patients and healthy controls. CD4 + T cells were isolated and cultured. Using quantitative PCR detect, the level of microRNA-145 and RUNX3 mRNA level in the CD4 + T cells from asthma patients and healthy controls, meanwhile, western blot was used to detect the RUNX3 protein level. Th1 or Th2 related cytokines were measured by enzyme-linked immunosorbent assay. Dual-Luciferase Reporter Assay was performed to confirm the correlation between microRNA-145 and RUNX3. MicroRNA-145 mimic or inhibitor was transfected in the CD4 + T cells and the changes of RUNX3 level, Th1 or Th2 related cytokines and the percentage of Th1 and Th2 were observed after transfection. MicroRNA-145 level of CD4 + T cells was higher with a lower RUNX3 expression in asthma patients. There is negative correlation between microRNA-145 and RUNX3. Th2 hyperactivity and Th1 deficiency was detected in the CD4 + T cells of asthma patients. Dual-Luciferase Reporter Assay has shown that RUNX3 is a target of microRNA. Up-regulation or down-regulation of miR-145 level caused RUNX3 expression changes in CD4 + T cells and influence the related cytokines. Inhibition of microRNA-145 may reverse the imbalance of Th1/Th2 in asthma patients. MicroRNA-145 could regulate the balance of Th1/Th2 through targeting the RUNX3 in asthma patients. MicroRNA-145 and RUNX3 may be used as biomarkers or targets in the diagnosis or therapy of asthma.

  5. Regulation of nasal airway homeostasis and inflammation in mice by SHP-1 and Th2/Th1 signaling pathways.

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    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.

  6. The immune microenvironment in cutaneous leishmaniasis.

    Science.gov (United States)

    Jabbour, M N; Issa, G; Charafeddine, K; Simaan, Y; Karam, M; Khalifeh, H; Habib, R; Khalifeh, I

    2015-06-01

    duration did not correlate with Ridley pattern. The significant decrease in CD1a expression is postulated by two mechanisms; either via direct CD1a receptor uptake by leishmania amastigotes and/or negative feedback inhibition of CD1a Langerhans cells by double-negative CD3 T-regulatory cells. Modulation of the immune microenvironment in cutaneous leishmaniasis represents a potential therapeutic and prophylactic target. © 2014 European Academy of Dermatology and Venereology.

  7. Morbidly obese human subjects have increased peripheral blood CD4 + T cells with skewing toward a Treg- and Th2-dominated phenotype

    NARCIS (Netherlands)

    K. van der Weerd (Kim); W.A. Dik (Willem); B. Schrijver (Benjamin); D.H. Schweitzer (Dave ); A.W. Langerak (Anton); H.A. Drexhage (Hemmo); R.M. Kiewiet-Kemper (Rosalie); M.O. van Aken (Maarten); A. van Huisstede (Astrid); J.J.M. van Dongen (Jacques); A.J. van der Lelij (Aart Jan); F.J.T. Staal (Frank); P.M. van Hagen (Martin)

    2012-01-01

    textabstractObesity is associated with local T-cell abnormalities in adipose tissue. Systemic obesity-related abnormalities in the peripheral blood T-cell compartment are not well defined. In this study, we investigated the peripheral blood T-cell compartment of morbidly obese and lean subjects. We

  8. The cytokine polymorphisms affecting Th1/Th2 increase the susceptibility to, and severity of, chronic ITP.

    Science.gov (United States)

    Takahashi, Noriyuki; Saitoh, Takayuki; Gotoh, Nanami; Nitta, Yasuhiro; Alkebsi, Lobna; Kasamatsu, Tetsuhiro; Minato, Yusuke; Yokohama, Akihiko; Tsukamoto, Norifumi; Handa, Hiroshi; Murakami, Hirokazu

    2017-05-16

    T-helper cell type 1 (Th1) polarization in chronic immune thrombocytopenia (cITP) has been reported at the protein and mRNA levels. We evaluated the impact of Th1/Th2 cytokine and cytokine receptor functional polymorphisms on both susceptibility to, and severity of, cITP. We analysed IFN-γ + 874 T/A, IFN-γR -611G/A, IL-4 -590C/T, and IL-4Rα Q576R polymorphisms in 126 cITP patients (male/female: 34/92; median age: 47.7 years) and 202 healthy control donors. Genotyping was determined by PCR and direct sequencing. The Th1/Th2 ratio was detected in peripheral blood mononuclear cells via flow cytometry. cITP patients had a higher frequency of the IL-4Rα 576 non-QQ genotype compared to healthy subjects (P = 0.04). cITP patients with the IFN-γ +874 non-AA genotype (high expression type) showed more severe thrombocytopenia than those with the AA genotype (P Th1/Th2 ratio than control patients (P Th1/Th2 ratio (P Th1/Th2 increase the susceptibility to, and severity of, chronic ITP.

  9. Multiparametric classification links tumor microenvironments with tumor cell phenotype.

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    Bojana Gligorijevic

    2014-11-01

    Full Text Available While it has been established that a number of microenvironment components can affect the likelihood of metastasis, the link between microenvironment and tumor cell phenotypes is poorly understood. Here we have examined microenvironment control over two different tumor cell motility phenotypes required for metastasis. By high-resolution multiphoton microscopy of mammary carcinoma in mice, we detected two phenotypes of motile tumor cells, different in locomotion speed. Only slower tumor cells exhibited protrusions with molecular, morphological, and functional characteristics associated with invadopodia. Each region in the primary tumor exhibited either fast- or slow-locomotion. To understand how the tumor microenvironment controls invadopodium formation and tumor cell locomotion, we systematically analyzed components of the microenvironment previously associated with cell invasion and migration. No single microenvironmental property was able to predict the locations of tumor cell phenotypes in the tumor if used in isolation or combined linearly. To solve this, we utilized the support vector machine (SVM algorithm to classify phenotypes in a nonlinear fashion. This approach identified conditions that promoted either motility phenotype. We then demonstrated that varying one of the conditions may change tumor cell behavior only in a context-dependent manner. In addition, to establish the link between phenotypes and cell fates, we photoconverted and monitored the fate of tumor cells in different microenvironments, finding that only tumor cells in the invadopodium-rich microenvironments degraded extracellular matrix (ECM and disseminated. The number of invadopodia positively correlated with degradation, while the inhibiting metalloproteases eliminated degradation and lung metastasis, consistent with a direct link among invadopodia, ECM degradation, and metastasis. We have detected and characterized two phenotypes of motile tumor cells in vivo, which

  10. Evidence of Immunosuppressive and Th2 Immune Polarizing Effects of Antidiabetic Momordica charantia Fruit Juice

    Science.gov (United States)

    Amoussa, Abdou Madjid; Adjagba, Marius; Lagnika, Latifou; Lalèyè, Anatole

    2017-01-01

    The mechanism of action of the antidiabetic capacity of Momordica charantia is still under investigation. Here, we assessed phytochemical compositions, antioxidant activity, and effects of total and filtered fruit and leafy stem juices of Momordica charantia on human T cell proliferation and differentiation through quantification of Th1/Th2 cytokines. In the absence of stimulation, total fruit and leafy stem juices induced significant T cell proliferation. Under PHA stimulation, both juices potentiated plant-induced T cell proliferation. However, the filtered fruit and leafy stem juices significantly inhibited PHA-stimulated T cell proliferation, while neither juice influenced T cell proliferation. Moreover, total and filtered fruit juice increased IL-4 secretion, while total and filtered leafy stem juice enhanced IFN-γ production. Phytochemical screening revealed the presence of tannins, flavonoids, anthocyans, steroids, and triterpenoids in both juices. Alkaloids, quinone derivatives, cardenolides, and cyanogenic derivatives were undetectable. The saponins present in total juices were undetectable after filtration. Moreover, both juices had appreciable antioxidant capacity. Our study supports the type 1 antidiabetic effect of filtered fruit juice of M. charantia which may be related to its immunosuppressive and T-helper 2 cell inducing capacities. Due to their immune-stimulatory activities and their ability to increase T-helper 1 cell cytokines, total fruit and leafy stem juices may serve in the treatment of immunodeficiency and certain infections. PMID:28812026

  11. Ingested (oral) SIRS peptide 1-21 inhibits acute EAE by inducing Th2-like cytokines.

    Science.gov (United States)

    Brod, Staley A; Hood, Zachary

    2007-02-01

    Ingested type I IFN inhibits clinical attacks, relapses and inflammation in murine chronic relapsing EAE by inhibiting Th1-like cytokines. Type I IFN activates human suppressor T cells that produce SIRS. We examined whether oral (ingested) SIRS peptide inhibits EAE by decreasing Th1-like cytokines. Parenteral SIRS peptide 1-21 showed a significant inhibition of disease severity in murine EAE. Ingested SIRS peptide at 10 and 100 microg SIRS peptide showed a significant inhibition of disease severity but also a prolonged delay in the onset of disease compared to placebo. There were significantly less inflammatory foci in the SIRS peptide fed group compared to the control mock fed group. Splenocytes from SIRS peptide 1-21 fed mice showed increased production of Th2-like CD30L, IL-13, TCA-3 cytokines/chemokines and decreased production of Th1-like cytokine lymphotactin. Ingested (oral) SIRS peptide significantly inhibits both clinical EAE and inflammation predominately via counter-regulatory type 2-like cytokines/chemokines IL-13, CD30L and TCA-3.

  12. 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.

  13. Schistosome-derived omega-1 drives Th2 polarization by suppressing protein synthesis following internalization by the mannose receptor

    Science.gov (United States)

    Everts, Bart; Hussaarts, Leonie; Driessen, Nicole N.; Meevissen, Moniek H.J.; Schramm, Gabriele; van der Ham, Alwin J.; van der Hoeven, Barbara; Scholzen, Thomas; Burgdorf, Sven; Mohrs, Markus; Pearce, Edward J.; Hokke, Cornelis H.; Haas, Helmut; Smits, Hermelijn H.

    2012-01-01

    Omega-1, a glycosylated T2 ribonuclease (RNase) secreted by Schistosoma mansoni eggs and abundantly present in soluble egg antigen, has recently been shown to condition dendritic cells (DCs) to prime Th2 responses. However, the molecular mechanisms underlying this effect remain unknown. We show in this study by site-directed mutagenesis of omega-1 that both the glycosylation and the RNase activity are essential to condition DCs for Th2 polarization. Mechanistically, we demonstrate that omega-1 is bound and internalized via its glycans by the mannose receptor (MR) and subsequently impairs protein synthesis by degrading both ribosomal and messenger RNA. These experiments reveal an unrecognized pathway involving MR and interference with protein synthesis that conditions DCs for Th2 priming. PMID:22966004

  14. Tomatidine Attenuates Airway Hyperresponsiveness and Inflammation by Suppressing Th2 Cytokines in a Mouse Model of Asthma

    Directory of Open Access Journals (Sweden)

    Chieh-Ying Kuo

    2017-01-01

    Full Text Available Tomatidine is isolated from the fruits of tomato plants and found to have anti-inflammatory effects in macrophages. In the present study, we investigated whether tomatidine suppresses airway hyperresponsiveness (AHR and eosinophil infiltration in asthmatic mice. BALB/c mice were sensitized with ovalbumin and treated with tomatidine by intraperitoneal injection. Airway resistance was measured by intubation analysis as an indication of airway responsiveness, and histological studies were performed to evaluate eosinophil infiltration in lung tissue. Tomatidine reduced AHR and decreased eosinophil infiltration in the lungs of asthmatic mice. Tomatidine suppressed Th2 cytokine production in bronchoalveolar lavage fluid. Tomatidine also blocked the expression of inflammatory and Th2 cytokine genes in lung tissue. In vitro, tomatidine inhibited proinflammatory cytokines and CCL11 production in inflammatory BEAS-2B bronchial epithelial cells. These results indicate that tomatidine contributes to the amelioration of AHR and eosinophil infiltration by blocking the inflammatory response and Th2 cell activity in asthmatic mice.

  15. Ascaris lumbricoides pseudocoelomic body fluid induces a partially activated dendritic cell phenotype with Th2 promoting ability in vivo.

    Science.gov (United States)

    Dowling, David J; Noone, Cariosa M; Adams, Paul N; Vukman, Krisztina V; Molloy, Sile F; Forde, Jessica; Asaolu, Samuel; O'Neill, Sandra M

    2011-02-01

    Dendritic cells (DCs) matured with helminth-derived molecules that promote Th2 immune responses do not follow conventional definitions of DC maturation processes. While a number of models of DC maturation by Th2 stimuli are postulated, further studies are required if we are to clearly define DC maturation processes that lead to Th2 immune responses. In this study, we examine the interaction of Th2-inducing molecules from the parasitic helminth Ascaris lumbricoides with the maturation processes and function of DCs. Here we show that murine bone marrow-derived DCs are partially matured by A. lumbricoides pseudocoelomic body fluid (ABF) as characterised by the production of IL-6, IL-12p40 and macrophage inflammatory protein 2 (MIP-2) but no enhanced expression of cluster of differentiation (CD)-14, T-cell co-stimulatory markers CD80, CD86, CD40, OX40L and major histocompatibility complex class II was observed. Despite these phenotypic characteristics, ABF-stimulated DCs displayed the functional hallmarks of fully matured cells, enhancing DC phagocytosis and promoting Th2-type responses in skin-draining lymph node cells in vivo. ABF activated Th2-associated extracellular signal-regulated kinase-1 and nuclear factor-kB intracellular signalling pathways independently of toll-like receptor 4. Taken together, we believe this is the first paper to demonstrate A. lumbricoides murine DC-Th cell-driven responses shedding further light on DC maturation processes by helminth antigens. Copyright © 2010 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

  16. Correlation Between Th1, Th2 Cells and Levels of Serum MMP-2, MMP-9 in Children with Asthma

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    Xuan WANG

    2015-12-01

    Full Text Available Abstract Objective: To explore the correlation between Th1 and Th2 cells and the levels of serum matrix metalloproteinase-2 (MMP-2 and MMP-9 in children with asthma. Methods: A total of 89 children with asthma were divided into acute group (n=48 and chronic group (n=41 according to the course of disease, and 40 healthy children at the same term were collected as control group. The ratios of Th1 and Th2 cells as well as levels of MMP-2 and MMP-9 were compared in three groups, and the correlation between Th1 and Th2 cells and levels of MMP-2, MMP-9 was analyzed in acute group and chronic group. Results: When compared with control group, the ratios of Th1 and Th2 cells went down in both acute group and chronic group (P<0.01, while the levels of serum MMP-2 and MMP-9 up (P<0.01. The levels of serum MMP-2 and MMP-9 in acute group were dramatically higher than those in chronic group, and there was statistical significance (P<0.01. Pearson correlation analysis revealed that there was no significant correlation between Th1 and Th2 cells and MMP-2 level (r=0.148, P=0.314, r=0.299, P=0.058; r=0.183, P=0.214, r=0.289, P=0.067, whereas both Th1 and Th2 cells were negatively correlated with MMP-9 level in acute group and chronic group (r=-0.489, P=0.000, r=-0.324, P=0.039; r=-0.352, P=0.014, r=-0.357, P=0.022. Conclusion: Aberrant secretion of Th cells can not only damage the immune function of children with asthma, but also decrease the level of serum MMP-9, consequently affecting the collagen degradation and airway remodeling.

  17. Chronic cat allergen exposure induces a TH2 cell-dependent IgG4 response related to low sensitization.

    Science.gov (United States)

    Renand, Amedee; Archila, Luis D; McGinty, John; Wambre, Erik; Robinson, David; Hales, Belinda J; Thomas, Wayne R; Kwok, William W

    2015-12-01

    In human subjects, allergen tolerance has been observed after high-dose allergen exposure or after completed allergen immunotherapy, which is related to the accumulation of anti-inflammatory IgG4. However, the specific T-cell response that leads to IgG4 induction during chronic allergen exposure remains poorly understood. We sought to evaluate the relationship between cat allergen-specific T-cell frequency, cat allergen-specific IgE and IgG4 titers, and clinical status in adults with cat allergy with and without cat ownership and the cellular mechanism by which IgG4 is produced. Fel d 1-, Fel d 4-, Fel d 7-, and Fel d 8-specific T-cell responses were characterized by CD154 expression after antigen stimulation. In allergic subjects without cat ownership, the frequency of cat allergen (Fel d 1 and Fel d 4)-specific TH2 (sTH2) cells correlates with higher IgE levels and is linked to asthma. Paradoxically, we observed that subjects with cat allergy and chronic cat exposure maintain a high frequency of sTH2 cells, which correlates with higher IgG4 levels and low sensitization. B cells from allergic, but not nonallergic subjects, are able to produce IgG4 after cognate interactions with sTH2 clones and Fel d 1 peptide or the Fel d 1 recombinant protein. These experiments suggest that (1) allergen-experienced B cells with the capacity to produce IgG4 are present in allergic subjects and (2) cat allergen exposure induces an IgG4 response in a TH2 cell-dependent manner. Thus IgG4 accumulation could be mediated by chronic activation of the TH2 response, which in turn drives desensitization. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. All rights reserved.

  18. Immunosuppression associated with chronic inflammation in the tumor microenvironment

    Science.gov (United States)

    Wang, Dingzhi; DuBois, Raymond N.

    2015-01-01

    Chronic inflammation contributes to cancer development via multiple mechanisms. One potential mechanism is that chronic inflammation can generate an immunosuppressive microenvironment that allows advantages for tumor formation and progression. The immunosuppressive environment in certain chronic inflammatory diseases and solid cancers is characterized by accumulation of proinflammatory mediators, infiltration of immune suppressor cells and activation of immune checkpoint pathways in effector T cells. In this review, we highlight recent advances in our understanding of how immunosuppression contributes to cancer and how proinflammatory mediators induce the immunosuppressive microenvironment via induction of immunosuppressive cells and activation of immune checkpoint pathways. PMID:26354776

  19. TRAF6 is essential for maintenance of regulatory T cells that suppress Th2 type autoimmunity.

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    Go Muto

    Full Text Available Regulatory T cells (Tregs maintain immune homeostasis by limiting inflammatory responses. TRAF6 plays a key role in the regulation of innate and adaptive immunity by mediating signals from various receptors including the T-cell receptor (TCR. T cell-specific deletion of TRAF6 has been shown to induce multiorgan inflammatory disease, but the role of TRAF6 in Tregs remains to be investigated. Here, we generated Treg-specific TRAF6-deficient mice using Foxp3-Cre and TRAF6-flox mice. Treg-specific TRAF6-deficient (cKO mice developed allergic skin diseases, arthritis, lymphadenopathy and hyper IgE phenotypes. Although TRAF6-deficient Tregs possess similar in vitro suppression activity compared to wild-type Tregs, TRAF6-deficient Tregs did not suppress colitis in lymphopenic mice very efficiently due to reduced number of Foxp3-positive cells. In addition, the fraction of TRAF6-deficient Tregs was reduced compared with wild-type Tregs in female cKO mice without inflammation. Moreover, adoptive transfer of Foxp3 (+ Tregs into Rag2(-/- mice revealed that TRAF6-deficient Tregs converted into Foxp3(- cells more rapidly than WT Tregs under lymphopenic conditions. Fate-mapping analysis also revealed that conversion of Tregs from Foxp3(+ to Foxp3(- (exFoxp3 cells was accelerated in TRAF6-deficient Tregs. These data indicate that TRAF6 in Tregs plays important roles in the maintenance of Foxp3 in Tregs and in the suppression of pathogenic Th2 type conversion of Tregs.

  20. 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.

  1. Profound tumor-specific Th2 bias in patients with malignant glioma

    International Nuclear Information System (INIS)

    Shimato, Shinji; Maier, Lisa M; Maier, Richard; Bruce, Jeffrey N; Anderson, Richard CE; Anderson, David E

    2012-01-01

    Vaccination against tumor-associated antigens is one promising approach to immunotherapy against malignant gliomas. While previous vaccine efforts have focused exclusively on HLA class I-restricted peptides, class II-restricted peptides are necessary to induce CD4 + helper T cells and sustain effective anti-tumor immunity. In this report we investigated the ability of five candidate peptide epitopes derived from glioma-associated antigens MAGE and IL-13 receptor α2 to detect and characterize CD4 + helper T cell responses in the peripheral blood of patients with malignant gliomas. Primary T cell responses were determined by stimulating freshly isolated PBMCs from patients with primary glioblastoma (GBM) (n = 8), recurrent GBM (n = 5), meningioma (n = 7), and healthy controls (n = 6) with each candidate peptide, as well as anti-CD3 monoclonal antibody (mAb) and an immunodominant peptide epitope derived from myelin basic protein (MBP) serving as positive and negative controls, respectively. ELISA was used to measure IFN-γ and IL-5 levels, and the ratio of IFN-γ/IL-5 was used to determine whether the response had a predominant Th1 or Th2 bias. We demonstrate that novel HLA Class-II restricted MAGE-A3 and IL-13Rα2 peptides can detect T cell responses in patients with GBMs as well as in healthy subjects. Stimulation with a variety of peptide antigens over-expressed by gliomas is associated with a profound reduction in the IFN-γ/IL-5 ratio in GBM patients relative to healthy subjects. This bias is more pronounced in patients with recurrent GBMs. Therapeutic vaccine strategies to shift tumor antigen-specific T cell response to a more immunostimulatory Th1 bias may be needed for immunotherapeutic trials to be more successful clinically

  2. Discovery of a [WO] central star in the planetary nebula Th 2-A

    Science.gov (United States)

    Weidmann, W. A.; Gamen, R.; Díaz, R. J.; Niemela, V. S.

    2008-09-01

    Context: About 2500 planetary nebulae are known in our Galaxy but only 224 have central stars with reported spectral types in the Strasbourg-ESO Catalogue of Galactic Planetary Nebulae (Acker et al. 1992; Acker et al. 1996). Aims: We have started an observational program aiming to increase the number of PN central stars with spectral classification. Methods: By means of spectroscopy and high resolution imaging, we identify the position and true nature of the central star. We carried out low resolution spectroscopic observations at CASLEO telescope, complemented with medium resolution spectroscopy performed at Gemini South and Magellan telescopes. Results: As a first outcome of this survey, we present for the first time the spectra of the central star of the PN Th 2-A. These spectra show emission lines of ionized C and O, typical in Wolf-Rayet stars. Conclusions: We identify the position of that central star, which is not the brightest one of the visual central pair. We classify it as of type [WO 3]pec, which is consistent with the high excitation and dynamical age of the nebula. Based on data collected at (i) the Complejo Astronómico El Leoncito (CASLEO), which is operated under agreement between the Consejo Nacional de Investigaciones Científicas y Técnicas de la República Argentina y Universidades Nacionales de La Plata, Córdoba y San Juan, Argentina; (ii) the 6.5 m Magellan Telescopes at Las Campanas Observatory, Chile; (iii) the 8 m Gemini South Telescope, Chile.

  3. Effects of small intestinal submucosa (SIS) on the murine innate immune microenvironment induced by heat-killed Staphylococcus aureus.

    Science.gov (United States)

    Roy Chowdhury, Roshni; Aachoui, Youssef; Ghosh, Swapan K

    2012-01-01

    The use of biological scaffold materials for wound healing and tissue remodeling has profoundly impacted regenerative medicine and tissue engineering. The porcine-derived small intestinal submucosa (SIS) is a licensed bioscaffold material regularly used in wound and tissue repair, often in contaminated surgical fields. Complications and failures due to infection of this biomaterial have therefore been a major concern and challenge. SIS can be colonized and infected by wound-associated bacteria, particularly Staphylococcus aureus. In order to address this concern and develop novel intervention strategies, the immune microenvironment orchestrated by the combined action of S. aureus and SIS should be critically evaluated. Since the outcome of tissue remodeling is largely controlled by the local immune microenvironment, we assessed the innate immune profile in terms of cytokine/chemokine microenvironment and inflammasome-responsive genes. BALB/c mice were injected intra-peritoneally with heat-killed S. aureus in the presence or absence of SIS. Analyses of cytokines, chemokines and microarray profiling of inflammasome-related genes were done using peritoneal lavages collected 24 hours after injection. Results showed that unlike SIS, the S. aureus-SIS interactome was characterized by a Th1-biased immune profile with increased expressions of IFN-γ, IL-12 and decreased expressions of IL-4, IL-13, IL-33 and IL-6. Such modulation of the Th1/Th2 axis can greatly facilitate graft rejections. The S. aureus-SIS exposure also augmented the expressions of pro-inflammatory cytokines like IL-1β, Tnf-α, CD30L, Eotaxin and Fractalkine. This heightened inflammatory response caused by S. aureus contamination could enormously affect the biocompatibility of SIS. However, the mRNA expressions of many inflammasome-related genes like Nlrp3, Aim2, Card6 and Pycard were down-regulated by heat-killed S. aureus with or without SIS. In summary, our study explored the innate immune

  4. Acidic Microenvironments in Waste Rock Characterized by Neutral Drainage: Bacteria–Mineral Interactions at Sulfide Surfaces

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    John W. Dockrey

    2014-03-01

    Full Text Available Microbial populations and microbe-mineral interactions were examined in waste rock characterized by neutral rock drainage (NRD. Samples of three primary sulfide-bearing waste rock types (i.e., marble-hornfels, intrusive, exoskarn were collected from field-scale experiments at the Antamina Cu–Zn–Mo mine, Peru. Microbial communities within all samples were dominated by neutrophilic thiosulfate oxidizing bacteria. However, acidophilic iron and sulfur oxidizers were present within intrusive waste rock characterized by bulk circumneutral pH drainage. The extensive development of microbially colonized porous Fe(III (oxyhydroxide and Fe(III (oxyhydroxysulfate precipitates was observed at sulfide-mineral surfaces during examination by field emission-scanning electron microscopy-energy dispersive X-ray spectroscopy (FE-SEM-EDS. Linear combination fitting of bulk extended X-ray absorption fine structure (EXAFS spectra for these precipitates indicated they were composed of schwertmannite [Fe8O8(OH6–4.5(SO41–1.75], lepidocrocite [γ-FeO(OH] and K-jarosite [KFe3(OH6(SO42]. The presence of schwertmannite and K-jarosite is indicative of the development of localized acidic microenvironments at sulfide-mineral surfaces. Extensive bacterial colonization of this porous layer and pitting of underlying sulfide-mineral surfaces suggests that acidic microenvironments can play an important role in sulfide-mineral oxidation under bulk circumneutral pH conditions. These findings have important implications for water quality management in NRD settings.

  5. Despite disorganized synapse structure, Th2 cells maintain directional delivery of CD40L to antigen-presenting B cells.

    Directory of Open Access Journals (Sweden)

    Jennifer L Gardell

    Full Text Available Upon recognition of peptide displayed on MHC molecules, Th1 and Th2 cells form distinct immunological synapse structures. Th1 cells have a bull's eye synapse structure with TCR/ MHC-peptide interactions occurring central to a ring of adhesion molecules, while Th2 cells have a multifocal synapse with small clusters of TCR/MHC interactions throughout the area of T cell/antigen-presenting cell interaction. In this study, we investigated whether this structural difference in the immunological synapse affects delivery of T cell help. The immunological synapse is thought to ensure antigen-specific delivery of cytolytic granules and killing of target cells by NK cells and cytolytic T cells. In helper T cells, it has been proposed that the immunological synapse may direct delivery of other effector molecules including cytokines. CD40 ligand (CD40L is a membrane-bound cytokine essential for antigen-specific T cell help for B cells in the antibody response. We incubated Th1 and Th2 cells overnight with a mixture of antigen-presenting and bystander B cells, and the delivery of CD40L to B cells and subsequent B cell responses were compared. Despite distinct immunological synapse structures, Th1 and Th2 cell do not differ in their ability to deliver CD40L and T cell help in an antigen-specific fashion, or in their susceptibility to inhibition of help by a blocking anti-CD40L antibody.

  6. Role of dendritic cells in Th1/Th2 balance: A novel therapeutic target of allergic diseases

    Directory of Open Access Journals (Sweden)

    Yusei Ohshima

    2004-01-01

    Full Text Available Considerable evidence supports the role of dendritic cells (DC in the pathogenesis of allergic diseases. Dendritic cells, as the most potent antigen-presenting cells (APC for the induction of primary immune response to antigen, are deeply involved in the differentiation of na'i've T cells into Th2 cells, thereby developing the development of allergic sensitization. After sensitization, DC may also function as a major APC to control the activation and clonal expansion of memory Th2 cells. In addition, DC are able to produce chemokines to recruit Th2 cells into inflammatory sites, indicating DC are important agents in various phases of allergic inflammation. Recently, we have demonstrated that monocyte chemotactic protein-1 not only regulates the homing of DC, but also modulates DC function. The present paper reviews the role of DC in the regulation of the Th2 response in allergic diseases and discusses the possibility of a new therapeutic strategy targeting chemokine-mediated regulation of DC function.

  7. Despite disorganized synapse structure, Th2 cells maintain directional delivery of CD40L to antigen-presenting B cells.

    Science.gov (United States)

    Gardell, Jennifer L; Parker, David C

    2017-01-01

    Upon recognition of peptide displayed on MHC molecules, Th1 and Th2 cells form distinct immunological synapse structures. Th1 cells have a bull's eye synapse structure with TCR/ MHC-peptide interactions occurring central to a ring of adhesion molecules, while Th2 cells have a multifocal synapse with small clusters of TCR/MHC interactions throughout the area of T cell/antigen-presenting cell interaction. In this study, we investigated whether this structural difference in the immunological synapse affects delivery of T cell help. The immunological synapse is thought to ensure antigen-specific delivery of cytolytic granules and killing of target cells by NK cells and cytolytic T cells. In helper T cells, it has been proposed that the immunological synapse may direct delivery of other effector molecules including cytokines. CD40 ligand (CD40L) is a membrane-bound cytokine essential for antigen-specific T cell help for B cells in the antibody response. We incubated Th1 and Th2 cells overnight with a mixture of antigen-presenting and bystander B cells, and the delivery of CD40L to B cells and subsequent B cell responses were compared. Despite distinct immunological synapse structures, Th1 and Th2 cell do not differ in their ability to deliver CD40L and T cell help in an antigen-specific fashion, or in their susceptibility to inhibition of help by a blocking anti-CD40L antibody.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

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

    2017-09-12

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

  10. Mast cells have no impact on cutaneous leishmaniasis severity and related Th2 differentiation in resistant and susceptible mice.

    Science.gov (United States)

    Paul, Christoph; Wolff, Svenja; Zapf, Thea; Raifer, Hartmann; Feyerabend, Thorsten B; Bollig, Nadine; Camara, Bärbel; Trier, Claudia; Schleicher, Ulrike; Rodewald, Hans-Reimer; Lohoff, Michael

    2016-01-01

    The genus leishmania comprises different protozoan parasites which are causative agents of muco-cutaneous and systemic, potentially lethal diseases. After infection with the species Leishmania major, resistant mice expand Th1 cells which stimulate macrophages for Leishmania destruction. In contrast, susceptible mice generate Th2 cells which deactivate macrophages, leading to systemic spread of the pathogens. Th-cell differentiation is determined within the first days, and Th2 cell differentiation requires IL-4, whereby the initial IL-4 source is often unknown. Mast cells are potential sources of IL-4, and hence their role in murine leishmaniasis has previously been studied in mast cell-deficient Kit mutant mice, although these mice display immunological phenotypes beyond mast cell deficiency. We therefore readdressed this question by infecting Kit-independent mast cell-deficient mice that are Th1 (C57BL/6 Cpa(Cre) ) or Th2 (BALB/c Cpa(Cre) ) prone with L. major. Using different parasite doses and intra- or subcutaneous infection routes, the results demonstrate no role of mast cells on lesion size development, parasite load, immune cell phenotypes expanding in draining lymph nodes, and cytokine production during murine cutaneous leishmaniasis. Thus, other cell types such as ILCs or T cells have to be considered as primary source of Th2-driving IL-4. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Hyperreactive onchocerciasis is characterized by a combination of Th17-Th2 immune responses and reduced regulatory T cells.

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    Gnatoulma Katawa

    2015-01-01

    Full Text Available Clinical manifestations in onchocerciasis range from generalized onchocerciasis (GEO to the rare but severe hyperreactive (HO/sowda form. Since disease pathogenesis is associated with host inflammatory reactions, we investigated whether Th17 responses could be related to aggravated pathology in HO. Using flow cytometry, filarial-specific cytokine responses and PCR arrays, we compared the immune cell profiles, including Th subsets, in individuals presenting the two polar forms of infection and endemic normals (EN. In addition to elevated frequencies of memory CD4+ T cells, individuals with HO showed accentuated Th17 and Th2 profiles but decreased CD4+CD25hiFoxp3+ regulatory T cells. These profiles included increased IL-17A+, IL-4+, RORC2+ and GATA3+CD4+ T cell populations. Flow cytometry data was further confirmed using a PCR array since Th17-related genes (IL-17 family members, IL-6, IL-1β and IL-22 and Th2-related (IL-4, IL-13, STAT6 genes were all significantly up-regulated in HO individuals. In addition, stronger Onchocerca volvulus-specific Th2 responses, especially IL-13, were observed in vitro in hyperreactive individuals when compared to GEO or EN groups. This study provides initial evidence that elevated frequencies of Th17 and Th2 cells form part of the immune network instigating the development of severe onchocerciasis.

  12. Cigarette smoking enhances T cell activation and a Th2 immune response; an aspect of the pathophysiology in periodontal disease

    NARCIS (Netherlands)

    Torres de Heens, G.L.; van der Velden, U.; Loos, B.G.

    2009-01-01

    Smoking is a strong risk factor for periodontitis. Treated patients who smoke show increased risk for further periodontal breakdown, despite receiving maintenance care. Previous work indicated that such patients have a monocytic cytokine response favoring Th2 activity. The purpose of this study was

  13. Cord blood Vα24-Vβ11 natural killer T cells display a Th2-chemokine receptor profile and cytokine responses.

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    Susanne Harner

    Full Text Available BACKGROUND: The fetal immune system is characterized by a Th2 bias but it is unclear how the Th2 predominance is established. Natural killer T (NKT cells are a rare subset of T cells with immune regulatory functions and are already activated in utero. To test the hypothesis that NKT cells are part of the regulatory network that sets the fetal Th2 predominance, percentages of Vα24(+Vβ11(+ NKT cells expressing Th1/Th2-related chemokine receptors (CKR were assessed in cord blood. Furthermore, IL-4 and IFN-γ secreting NKT cells were quantified within the single CKR(+ subsets. RESULTS: Cord blood NKT cells expressed the Th2-related CCR4 and CCR8 at significantly higher frequencies compared to peripheral blood NKT cells from adults, while CXCR3(+ and CCR5(+ cord blood NKT cells (Th1-related were present at lower percentages. Within CD4(negCD8(neg (DN NKT cells, the frequency of IL-4 producing NKT cells was significantly higher in cord blood, while frequencies of IFN-γ secreting DN NKT cells tended to be lower. A further subanalysis showed that the higher percentage of IL-4 secreting DN NKT cells was restricted to CCR3(+, CCR4(+, CCR5(+, CCR6(+, CCR7(+, CCR8(+ and CXCR4(+ DN subsets in cord blood. This resulted in significantly decreased IFN-γ /IL-4 ratios of CCR3(+, CCR6(+ and CCR8(+ cord blood DN NKT cells. Sequencing of VA24AJ18 T cell receptor (TCR transcripts in sorted cord blood Vα24Vβ11 cells confirmed the invariant TCR alpha-chain ruling out the possibility that these cells represent an unusual subset of conventional T cells. CONCLUSIONS: Despite the heterogeneity of cord blood NKT cells, we observed a clear Th2-bias at the phenotypic and functional level which was mainly found in the DN subset. Therefore, we speculate that NKT cells are important for the initiation and control of the fetal Th2 environment which is needed to maintain tolerance towards self-antigens as well as non-inherited maternal antigens.

  14. Toll-like receptor-2 agonist-allergen coupling efficiently redirects Th2 cell responses and inhibits allergic airway eosinophilia.

    Science.gov (United States)

    Krishnaswamy, Jayendra Kumar; Jirmo, Adan Chari; Baru, Abdul Mannan; Ebensen, Thomas; Guzmán, Carlos A; Sparwasser, Tim; Behrens, Georg M N

    2012-12-01

    Toll-like receptor (TLR) agonists beneficially modulate allergic airway inflammation. However, the efficiency of TLR agonists varies considerably, and their exact cellular mechanisms (especially of TLR 2/6 agonists) are incompletely understood. We investigated at a cellular level whether the administration of the pharmacologically improved TLR2/6 agonist S-[2,3-bispalmitoyiloxy-(2R)-propyl]-R-cysteinyl-amido-monomethoxy polyethylene glycol (BPP) conjugated to antigenic peptide (BPP-OVA) could divert an existing Th2 response and influence airway eosinophilia. The effects of BPP-OVA on airway inflammation were assessed in a classic murine sensitization/challenge model and an adoptive transfer model, which involved the adoptive transfer of in vitro differentiated ovalbumin (OVA)-specific Th2 cells. Functional T-cell stimulation by lung dendritic cells (DCs) was determined both in vitro and in vivo, combined with a cytokine secretion analysis. A single mucosal application of BPP-OVA efficiently delivered antigen, led to TLR2-mediated DC activation, and resulted in OVA-specific T-cell proliferation via lung DCs in vivo. In alternative models of allergic airway disease, a single administration of BPP-OVA before OVA challenge (but not BPP alone) significantly reduced airway eosinophilia, most likely through altered antigen-specific T-cell stimulation via DCs. Analyses of adoptively transferred Th2-biased cells after BPP-OVA administration in vivo suggested that BPP-OVA guides antigen-specific Th2 cells to produce significantly higher amounts of IFN-γ upon allergen challenge. In conclusion, our data show for the first time that a single mucosal administration of a TLR 2/6 agonist-allergen conjugate can provoke IFN-γ responses in Th2-biased cells and alleviate allergic airway inflammation.

  15. Exosomic microRNAs in the tumor microenvironment

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    Paolo eNeviani

    2015-07-01

    Full Text Available Dissecting the cross talk between tumor cells and tumor microenvironment is quickly becoming the new frontier in cancer research. It is now widely accepted that cancer cells can exert a profound influence over their surroundings, by changing the microenvironment from a normal to a tumor-supportive state that allows for sustained tumor-growth, invasion and drug-resistance. Extracellular vesicles, especially exosomes, are recognized as a new category of intercellular communicator and they are emerging as of primary importance in controlling the interplay between the tumor and its environment. Exosomes derived from cancer cells or from cells of the tumor microenvironment allow for the horizontal transfer of information by virtue of their cargo, made of functional proteins and nucleic acids that are specifically sorted and loaded in exosomes during their biogenesis. In this review we will discuss the current knowledge regarding the role invested by microRNAs, a family of short non-coding RNAs frequently deregulated in malignancies and present in exosomes, in shaping the microenvironment in a cancer-dependent manner.

  16. Effects of ground insulation and greenhouse microenvironment on ...

    African Journals Online (AJOL)

    A study was conducted at Egerton University, Njoro, Kenya to establish the potential of plastic digester to produce biogas under natural and greenhouse microenvironment. The specific objectives were to evaluate the effects of greenhouse and ground insulation on the rate and quality of biogas generation. A greenhouse ...

  17. How Signaling Molecules Regulate Tumor Microenvironment: Parallels to Wound Repair

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    Peter Gál

    2017-10-01

    Full Text Available It is now suggested that the inhibition of biological programs that are associated with the tumor microenvironment may be critical to the diagnostics, prevention and treatment of cancer. On the other hand, a suitable wound microenvironment would accelerate tissue repair and prevent extensive scar formation. In the present review paper, we define key signaling molecules (growth factors, cytokines, chemokines, and galectins involved in the formation of the tumor microenvironment that decrease overall survival and increase drug resistance in cancer suffering patients. Additional attention will also be given to show whether targeted modulation of these regulators promote tissue regeneration and wound management. Whole-genome transcriptome profiling, in vitro and animal experiments revealed that interleukin 6, interleukin 8, chemokine (C-X-C motif ligand 1, galectin-1, and selected proteins of the extracellular matrix (e.g., fibronectin do have similar regulation during wound healing and tumor growth. Published data demonstrate remarkable similarities between the tumor and wound microenvironments. Therefore, tailor made manipulation of cancer stroma can have important therapeutic consequences. Moreover, better understanding of cancer cell-stroma interaction can help to improve wound healing by supporting granulation tissue formation and process of reepithelization of extensive and chronic wounds as well as prevention of hypertrophic scars and formation of keloids.

  18. Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Jaehong Kim

    2016-01-01

    Full Text Available Distinct tumor microenvironment forms in each progression step of cancer and has diverse capacities to induce both adverse and beneficial consequences for tumorigenesis. It is now known that immune cells can be activated to favor tumor growth and progression, most probably influenced by the tumor microenvironment. Tumor-associated macrophages and tumor-associated neutrophils can exert protumoral functions, enhancing tumor cell invasion and metastasis, angiogenesis, and extracellular matrix remodeling, while inhibiting the antitumoral immune surveillance. Considering that neutrophils in inflammatory environments recruit macrophages and that recruited macrophages affect neutrophil functions, there may be various degrees of interaction between tumor-associated macrophages and tumor-associated neutrophils. Platelets also play an important role in the recruitment and regulation of monocytic and granulocytic cells in the tumor tissues, suggesting that platelet function may be essential for generation of tumor-associated macrophages and tumor-associated neutrophils. In this review, we will explore the biology of tumor-associated macrophages and tumor-associated neutrophils and their possible interactions in the tumor microenvironment. Special attention will be given to the recruitment and activation of these tumor-associated cells and to the roles they play in maintenance of the tumor microenvironment and progression of tumors.

  19. Microenvironments and microscale productivity of cyanobacterial desert crusts

    Science.gov (United States)

    Garcia-Pichel, F.; Belnap, Jayne

    1996-01-01

    We used microsensors to characterize physicochemical microenvironments and photosynthesis occurring immediately after water saturation in two desert soil crusts from southeastern Utah, which were formed by the cyanobacteria Microcoleus vaginatus Gomont, Nostoc spp., and Scytonema sp. The light fields within the crusts presented steep vertical gradients in magnitude and spectral composition. Near-surface light-trapping zones were formed due to the scattering nature of the sand particles, but strong light attenuation resulted in euphotic zones only ca. 1 mm deep, which were progressively enriched in longer wavelengths with depth. Rates of gross photosynthesis (3.4a??9.4 mmol O2A?ma??2A?ha??1) and dark respiration (0.81a??3.1 mmol Oa??2A?ma??2A?ha??1) occurring within 1 to several mm from the surface were high enough to drive the formation of marked oxygen microenvironments that ranged from oxygen supersaturation to anoxia. The photosynthetic activity also resulted in localized pH values in excess of 10, 2a??3 units above the soil pH. Differences in metabolic parameters and community structure between two types of crusts were consistent with a successional pattern, which could be partially explained on the basis of the microenvironments. We discuss the significance of high metabolic rates and the formation of microenvironments for the ecology of desert crusts, as well as the advantages and limitations of microsensor-based methods for crust investigation.

  20. Operation of the computer model for microenvironment atomic oxygen exposure

    Science.gov (United States)

    Bourassa, R. J.; Gillis, J. R.; Gruenbaum, P. E.

    1995-01-01

    A computer model for microenvironment atomic oxygen exposure has been developed to extend atomic oxygen modeling capability to include shadowing and reflections. The model uses average exposure conditions established by the direct exposure model and extends the application of these conditions to treat surfaces of arbitrary shape and orientation.

  1. How Signaling Molecules Regulate Tumor Microenvironment: Parallels to Wound Repair.

    Science.gov (United States)

    Gál, Peter; Varinská, Lenka; Fáber, Lenka; Novák, Štepán; Szabo, Pavol; Mitrengová, Petra; Mirossay, Andrej; Mučaji, Pavel; Smetana, Karel

    2017-10-26

    It is now suggested that the inhibition of biological programs that are associated with the tumor microenvironment may be critical to the diagnostics, prevention and treatment of cancer. On the other hand, a suitable wound microenvironment would accelerate tissue repair and prevent extensive scar formation. In the present review paper, we define key signaling molecules (growth factors, cytokines, chemokines, and galectins) involved in the formation of the tumor microenvironment that decrease overall survival and increase drug resistance in cancer suffering patients. Additional attention will also be given to show whether targeted modulation of these regulators promote tissue regeneration and wound management. Whole-genome transcriptome profiling, in vitro and animal experiments revealed that interleukin 6, interleukin 8, chemokine (C-X-C motif) ligand 1, galectin-1, and selected proteins of the extracellular matrix (e.g., fibronectin) do have similar regulation during wound healing and tumor growth. Published data demonstrate remarkable similarities between the tumor and wound microenvironments. Therefore, tailor made manipulation of cancer stroma can have important therapeutic consequences. Moreover, better understanding of cancer cell-stroma interaction can help to improve wound healing by supporting granulation tissue formation and process of reepithelization of extensive and chronic wounds as well as prevention of hypertrophic scars and formation of keloids.

  2. Functional live cell imaging of the pulmonary neuroepithelial body microenvironment

    NARCIS (Netherlands)

    De Proost, Ian; Pintelon, Isabel; Brouns, Inge; Kroese, A; Riccardi, Daniela; Kemp, Paul J.; Timmermans, Jean-Pierre; Adriaensen, Dirk

    Pulmonary neuroepithelial bodies (NEBs) are densely innervated groups of neuroendocrine cells invariably accompanied by Clara-like cells. Together with NEBs, Clara-like cells form the so-called "NEB microenvironment," which recently has been assigned a potential pulmonary stem cell niche. Conclusive

  3. Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets

    NARCIS (Netherlands)

    W. van Ewijk (Willem); G. Hollander; C. Terhorst; B. Wang (Baoping)

    2000-01-01

    textabstractT-cell development is under the tight control of thymic microenvironments. Conversely, the integrity of thymic microenvironments depends on the physical presence of developing thymocytes, a phenomenon designated as 'thymic crosstalk'. We now show, using

  4. Effect of low dose radiation on Th1 and Th2 of thymocytes and splenocytes in mice

    International Nuclear Information System (INIS)

    Bai Ou; Liu Shuzheng; Mu Ying

    1998-01-01

    Objective: To elucidate the possible mechanism of activation of helper T cells after low dose radiation (LDR) exposure, the influence of whole-body irradiation (WBI) with 75 mGy X-rays on Th1 and Th2 was studied. Methods: Mice were irradiated at a dose rate of 12.5 mGy/min, and IFN-γ and IL-6 mRNA levels of the myocytes and splenocytes were analyzed by dot blot and Northern blot hybridization. Results: It was found that IFN-γ and IL-6 mRNA significantly increased after WBI with 75 mGy X-rays. Conclusion: The gene induction of cytokine profile after LDR indicates that activation of both Th1 and Th2 subtypes may be involved in the stimulation of immune functions by LDR

  5. Co-ordinate expression of Th1/Th2 phenotypes in maternal and fetal blood: evidence for a transplacental nexus.

    Science.gov (United States)

    Tse, Doris B; Young, Bruce K

    2012-01-06

    If maternal atopy and environmental exposure affect prenatal Th cell development, the maternal and fetal immune systems should display common Th1/Th2 phenotypes. To test this hypothesis, we studied maternal and neonatal blood samples from mothers with total serum IgE ordinate IFN-γ production from paired maternal and fetal mononuclear cells, accompanied by co-ordinate increases in activated CD4+CD69+ cells that display the CCR4+Th2 and CXCR3+ Th1 phenotypes. Maternal and fetal CD4+CXCR3+ T cells were subsequently identified as the major producers of IFN-γ. The data established that a transplacental nexus exists during normal pregnancy and that fetal Th cell responses may be biased by the maternal immune system.

  6. TEC and MAPK Kinase Signalling Pathways in T helper (TH) cell Development, TH2 Differentiation and Allergic Asthma

    Science.gov (United States)

    Kannan, Yashaswini; Wilson, Mark S.

    2013-01-01

    Significant advances in our understanding of the signalling events during T cell development and differentiation have been made in the past few decades. It is clear that ligation of the T cell receptor (TCR) triggers a series of proximal signalling cascades regulated by an array of protein kinases. These orchestrated and highly regulated series of events, with differential requirements of particular kinases, highlight the disparities between αβ+CD4+ T cells. Throughout this review we summarise both new and old studies, highlighting the role of Tec and MAPK in T cell development and differentiation with particular focus on T helper 2 (TH2) cells. Finally, as the allergy epidemic continues, we feature the role played by TH2 cells in the development of allergy and provide a brief update on promising kinase inhibitors that have been tested in vitro, in pre-clinical disease models in vivo and into clinical studies. PMID:24116341

  7. Searching for world domination

    CERN Multimedia

    Quillen, E

    2004-01-01

    "Optimists might believe Microsoft suffered a setback last week that will impede its progress toward world domination, but I suspect the company has already found a way to prevail. At issue before the European Union was Microsoft's bundling of its Windows Media Player with its operating system" (1 page)

  8. Iron dominated magnets

    International Nuclear Information System (INIS)

    Fischer, G.E.

    1985-07-01

    These two lectures on iron dominated magnets are meant for the student of accelerator science and contain general treatments of the subjects design and construction. The material is arranged in the categories: General Concepts and Cost Considerations, Profile Configuration and Harmonics, Magnetic Measurements, a few examples of ''special magnets'' and Materials and Practices. Extensive literature is provided

  9. Autosomal dominant polycystisk nyresygdom

    DEFF Research Database (Denmark)

    Naver, Signe Vinsand; Ørskov, Bjarne; Jensen, Anja Møller

    2017-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder which causes end stage renal disease. In Denmark, estimated 5,000 patients are living with the disease. Most of the patients are in regular contact with physicians due to the progression of kidney failure...

  10. Chemokines fail to up-regulate beta 1 integrin-dependent adhesion in human Th2 T lymphocytes.

    Science.gov (United States)

    Clissi, B; D'Ambrosio, D; Geginat, J; Colantonio, L; Morrot, A; Freshney, N W; Downward, J; Sinigaglia, F; Pardi, R

    2000-03-15

    Th1 and Th2 cells are functionally distinct subsets of CD4+ T lymphocytes whose tissue-specific homing to sites of inflammation is regulated in part by the differential expression of P- and E-selectin ligands and selected chemokine receptors. Here we investigated the expression and function of beta 1 integrins in Th1 and Th2 cells polarized in vitro. Th1 lymphocytes adhere transiently to the extracellular matrix ligands laminin 1 and fibronectin in response to chemokines such as RANTES and stromal cell-derived factor-1, and this process is paralleled by the activation of the Rac1 GTPase and by a rapid burst of actin polymerization. Selective inhibitors of phosphoinositide-3 kinase prevent efficiently all of the above processes, whereas the protein kinase C inhibitor bisindolylmaleimide prevents chemokine-induced adhesion without affecting Rac1 activation and actin polymerization. Notably, chemokine-induced adhesion to beta 1 integrin ligands is markedly reduced in Th2 cells. Such a defect cannot be explained by a reduced sensitivity to chemokine stimulation in this T cell subset, nor by a defective activation of the signaling cascade involving phosphoinositide-3 kinase, Rac1, and actin turnover, as all these processes are activated at comparable levels by chemokines in the two subsets. We propose that reduced beta 1 integrin-mediated adhesion in Th2 cells may restrain their ability to invade and/or reside in sites of chronic inflammation, which are characterized by thickening of basement membranes and extensive fibrosis, requiring efficient interaction with organized extracellular matrices.

  11. The diagnostic value of Th1/Th2 cell cytokine and thyroid autoantibody on autoimmune thyroid diseases

    International Nuclear Information System (INIS)

    Feng Xuemin; Qin Mingxiu; Zhao Yan

    2008-01-01

    To study the diagnostic value of Th1/Th2 cell cytokine and thyroid autoantibody in autoimmune thyroid diseases (AITD), 28 patients with Graves' disease (GD), 15 patients with hyperthyroidism and thyroiditis (GDIII), 13 patients with Hashimoto's hyperthyroidism (HTL), 21 patients with Hashimoto's thyroiditis(HT)and 20 healthy subjects were enrolled in this study. The serum concentrations of Th1 cytokine (IFN-γ) and Th2 cytokine (IL-4) were determined by ELISA. The serum levels of thyrotropin receptor antibodies (TRAb), thyroglobulin antibodies (TGAb) and thyroid peroxidase antibodies (TPOAb) were measured by RIA. The relationship between the serum levels of IFN-γ, IL-4 and TRAb, TGAb and TPOAb were analyzed. The results showed that IFN-γ levels from higher to lower in different groups were in the order of HT, HTL, GDIII, GD and the IL-4 were GD, GDIII, HTL, HT, respectively. There was significant difference in the IFN-γ (P<0.05) and IL-4 levels (P<0.01) between GDIII and HTL groups. There was no significant difference in TGAb and TPOAb between GDIII and HTL groups. In HT group, IFN-γ levels was positively correlated with TGAb and TPOAb (r=0.67,0.54,P<0.01). In GD group, IL-4 was positively correlated with TRAb (r =0.71,P<0.01). The imbalance of Th1/Th2 cell cytokine reflects pathologic change and abnormality of immune function in AITD patients. The detection of Th1/Th2 cell cytokine combined with thyroid autoantibody may be regarded as an indicator in the diagnosis of autoimmune thyroid diseases. (authors)

  12. Effects of Malassezia yeasts on serum Th1 and Th2 cytokines in patients with guttate psoriasis.

    Science.gov (United States)

    Aydogan, Kenan; Tore, Okan; Akcaglar, Sevim; Oral, Barbaros; Ener, Beyza; Tunalı, Sukran; Saricaoglu, Hayriye

    2013-01-01

    Systemic and focal infections caused by microorganisms have been known to induce or exacerbate psoriasis. Although the role of yeast species of the genus Malassezia in the pathogenesis of psoriasis is not fully understood, it is thought that these lipophilic yeasts may represent a triggering factor in the exacerbation of psoriatic lesions. This study investigated the effects of Malassezia yeasts on serum Th1 and Th2 cytokines in patients with guttate psoriasis (GP) in order to define their role in the pathogenesis of psoriasis. Fifty patients with GP and 29 clinically healthy individuals were included in the study. All samples consisted of scales and scrapings taken from the scalps, trunks, and upper limbs of both psoriasis patients and healthy subjects. Psoriasis patients and healthy subjects were grouped according to their positivity or negativity for Malassezia yeasts as ascertained by direct microscopy and/or culture. An enzyme-linked immunosorbent assay (ELISA) was used to measure serum levels of Th1 and Th2 cytokines in these groups. No significant differences in positivity for Malassezia yeasts were found between psoriatic skin and healthy skin in samples taken from different body sites. Serum interleukin-13 (IL-13) levels were significantly lower in the psoriasis group compared with the control group (P = 0.04). Levels of other cytokines did not differ significantly between the psoriasis and control groups. Mean levels of Th2 cytokines (IL-4, IL-10, IL-13), but not of Th1 cytokines (IL-2 and IFN-γ), were significantly lower in psoriasis patients positive for Malassezia yeasts compared with those negative for Malassezia yeasts and control subjects (P = 0.04, P Malassezia yeasts from GP lesions does not necessarily mean that these species are pathogenic, but their downregulating effects on anti-inflammatory Th2 cytokines may contribute to the occurrence of GP. © 2012 The International Society of Dermatology.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. 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.

  15. Review of microfluidic cell culture devices for the control of gaseous microenvironments in vitro

    Science.gov (United States)

    Wu, H.-M.; Lee, T.-A.; Ko, P.-L.; Chiang, H.-J.; Peng, C.-C.; Tung, Y.-C.

    2018-04-01

    Gaseous microenvironments play important roles in various biological activities in vivo. However, it is challenging to precisely control gaseous microenvironments in vitro for cell culture due to the high diffusivity nature of gases. In recent years, microfluidics has paved the way for the development of new types of cell culture devices capable of manipulating cellular microenvironments, and provides a powerful tool for in vitro cell studies. This paper reviews recent developments of microfluidic cell culture devices for the control of gaseous microenvironments, and discusses the advantages and limitations of current devices. We conclude with suggestions for the future development of microfluidic cell culture devices for the control of gaseous microenvironments.

  16. Pneumocystis-Driven Inducible Bronchus-Associated Lymphoid Tissue Formation Requires Th2 and Th17 Immunity.

    Science.gov (United States)

    Eddens, Taylor; Elsegeiny, Waleed; Garcia-Hernadez, Maria de la Luz; Castillo, Patricia; Trevejo-Nunez, Giraldina; Serody, Katelin; Campfield, Brian T; Khader, Shabaana A; Chen, Kong; Rangel-Moreno, Javier; Kolls, Jay K

    2017-03-28

    Inducible bronchus-associated lymphoid tissue (iBALT) is an ectopic lymphoid structure composed of highly organized T cell and B cell zones that forms in the lung in response to infectious or inflammatory stimuli. Here, we develop a model for fungal-mediated iBALT formation, using infection with Pneumocystis that induces development of pulmonary lymphoid follicles. Pneumocystis-dependent iBALT structure formation and organization required CXCL13 signaling. Cxcl13 expression was regulated by interleukin (IL)-17 family members, as Il17ra -/- , Il17rb -/- , and Il17rc -/- mice failed to develop iBALT. Interestingly, Il17rb -/- mice have intact Th17 responses, but failed to generate an anti-Pneumocystis Th2 response. Given a role for Th2 and Th17 immunity in iBALT formation, we demonstrated that primary pulmonary fibroblasts synergistically upregulated Cxcl13 transcription following dual stimulation with IL-13 and IL-17A in a STAT3/GATA3-dependent manner. Together, these findings uncover a role for Th2/Th17 cells in regulating Cxcl13 expression and provide an experimental model for fungal-driven iBALT formation. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  17. Mode of dendritic cell activation: the decisive hand in Th2/Th17 cell differentiation. Implications in asthma severity?

    Science.gov (United States)

    Vroman, Heleen; van den Blink, Bernt; Kool, Mirjam

    2015-02-01

    Asthma is a heterogeneous chronic inflammatory disease of the airways, with reversible airflow limitations and airway remodeling. The classification of asthma phenotypes was initially based on different combinations of clinical symptoms, but they are now unfolding to link biology to phenotype. As such, patients can suffer from a predominant eosinophilic, neutrophilic or even mixed eosinophilic/neutrophilic inflammatory response. In adult asthma patients, eosinophilic inflammation is usually seen in mild-to-moderate disease and neutrophilic inflammation in more severe disease. The underlying T cell response is predominated by T helper (Th) 2, Th17, or a mixed Th2/Th17 cell immune response. Dendritic cells (DCs) are "professional" antigen presenting cells (APCs), since their principal function is to present antigens and induce a primary immune response in resting naive T cells. DCs also drive the differentiation into distinctive Th subsets. The expression of co-stimulatory molecules and cytokines by DCs and surrounding cells determines the outcome of Th cell differentiation. The nature of DC activation will determine the expression of specific co-stimulatory molecules and cytokines, specifically needed for induction of the different Th cell programs. Thus DC activation is crucial for the subsequent effector Th immune responses. In this review, we will discuss underlying mechanisms that initiate DC activation in favor of Th2 differentiation versus Th1/Th17 and Th17 differentiation in the development of mild versus moderate to severe asthma. Copyright © 2014 Elsevier GmbH. All rights reserved.

  18. Immunoregulatory Effects of Paeoniflorin Exerts Anti-asthmatic Effects via Modulation of the Th1/Th2 Equilibrium.

    Science.gov (United States)

    Zhang, Tianzhu; Yang, Zhaocong; Yang, Shihai; Du, Juan; Wang, Shumin

    2015-12-01

    Paeoniflorin has been demonstrated to exert anti-inflammatory and immunomodulatory effects in the animal study. In this study, we investigated immunoregulatory effects of paeoniflorin on anti-asthmatic effects and underlying mechanisms. Asthma model was established by ovalbumin-induced. A total of 50 mice were randomly assigned to five experimental groups: control, model, dexamethasone (2 mg/kg), and paeoniflorin (10 and 20 mg/kg). Airway resistance (Raw) were measured by the forced oscillation technique; histological studies were evaluated by the hematoxylin and eosin (HE) staining; Th1/Th2 cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA); Th1/Th2 cells were evaluated by flow cytometry (FCM); and GATA3 and T-bet were evaluated by Western blot. Our study demonstrated that, compared with model group, paeoniflorin inhibited ovalbumin (OVA)-induced increases in Raw and eosinophil count; interleukin (IL)-4, IgE levels were recovered in bronchoalveolar lavage fluid compared; increased IFN-γ level in bronchoalveolar lavage fluid; histological studies demonstrated that paeoniflorin substantially inhibited OVA-induced eosinophilia in lung tissue and lung tissue compared with model group. Flow cytometry studies demonstrated that paeoniflorin can regulate Th1/Th2 balance. These findings suggest that paeoniflorin may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma.

  19. Human B cells induce dendritic cell maturation and favour Th2 polarization by inducing OX-40 ligand

    Science.gov (United States)

    Maddur, Mohan S.; Sharma, Meenu; Hegde, Pushpa; Stephen-Victor, Emmanuel; Pulendran, Bali; Kaveri, Srini V.; Bayry, Jagadeesh

    2015-01-01

    Dendritic cells (DCs) play a critical role in immune homeostasis by regulating the functions of various immune cells, including T and B cells. Notably, DCs also undergo education on reciprocal signalling by these immune cells and environmental factors. Various reports demonstrated that B cells have profound regulatory functions, although only few reports have explored the regulation of human DCs by B cells. Here we demonstrate that activated but not resting B cells induce maturation of DCs with distinct features to polarize Th2 cells that secrete interleukin (IL)-5, IL-4 and IL-13. B-cell-induced maturation of DCs is contact dependent and implicates signalling of B-cell activation molecules CD69, B-cell-activating factor receptor, and transmembrane activator and calcium-modulating cyclophilin ligand interactor. Mechanistically, differentiation of Th2 cells by B-cell-matured DCs is dependent on OX-40 ligand. Collectively, our results suggest that B cells have the ability to control their own effector functions by enhancing the ability of human DCs to mediate Th2 differentiation. PMID:24910129

  20. The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and Th2-type effector differentiation.

    Science.gov (United States)

    Carr, Tiffany; Krishnamoorthy, Veena; Yu, Shuyang; Xue, Hai-Hui; Kee, Barbara L; Verykokakis, Mihalis

    2015-05-04

    Invariant natural killer T cells (iNKT cells) are innate-like T cells that rapidly produce cytokines that impact antimicrobial immune responses, asthma, and autoimmunity. These cells acquire multiple effector fates during their thymic development that parallel those of CD4(+) T helper cells. The number of Th2-type effector iNKT cells is variable in different strains of mice, and their number impacts CD8 T, dendritic, and B cell function. Here we demonstrate a unique function for the transcription factor lymphoid enhancer factor 1 (LEF1) in the postselection expansion of iNKT cells through a direct induction of the CD127 component of the receptor for interleukin-7 (IL-7) and the transcription factor c-myc. LEF1 also directly augments expression of the effector fate-specifying transcription factor GATA3, thus promoting the development of Th2-like effector iNKT cells that produce IL-4, including those that also produce interferon-γ. Our data reveal LEF1 as a central regulator of iNKT cell number and Th2-type effector differentiation. © 2015 Carr et al.

  1. Engineering three-dimensional cell mechanical microenvironment with hydrogels.

    Science.gov (United States)

    Huang, Guoyou; Wang, Lin; Wang, Shuqi; Han, Yulong; Wu, Jinhui; Zhang, Qiancheng; Xu, Feng; Lu, Tian Jian

    2012-12-01

    Cell mechanical microenvironment (CMM) significantly affects cell behaviors such as spreading, migration, proliferation and differentiation. However, most studies on cell response to mechanical stimulation are based on two-dimensional (2D) planar substrates, which cannot mimic native three-dimensional (3D) CMM. Accumulating evidence has shown that there is a significant difference in cell behavior in 2D and 3D microenvironments. Among the materials used for engineering 3D CMM, hydrogels have gained increasing attention due to their tunable properties (e.g. chemical and mechanical properties). In this paper, we provide an overview of recent advances in engineering hydrogel-based 3D CMM. Effects of mechanical cues (e.g. hydrogel stiffness and externally induced stress/strain in hydrogels) on cell behaviors are described. A variety of approaches to load mechanical stimuli in 3D hydrogel-based constructs are also discussed.

  2. Engineering mechanical microenvironment of macrophage and its biomedical applications.

    Science.gov (United States)

    Li, Jing; Li, Yuhui; Gao, Bin; Qin, Chuanguang; He, Yining; Xu, Feng; Yang, Hui; Lin, Min

    2018-03-01

    Macrophages are the most plastic cells in the hematopoietic system and can be widely found in almost all tissues. Recently studies have shown that mechanical cues (e.g., matrix stiffness and stress/strain) can significantly affect macrophage behaviors. Although existing reviews on the physical and mechanical cues that regulate the macrophage's phenotype are available, engineering mechanical microenvironment of macrophages in vitro as well as a comprehensive overview and prospects for their biomedical applications (e.g., tissue engineering and immunotherapy) has yet to be summarized. Thus, this review provides an overview on the existing methods for engineering mechanical microenvironment of macrophages in vitro and then a section on their biomedical applications and further perspectives are presented.

  3. A study for radiation-related tumor microenvironment

    International Nuclear Information System (INIS)

    Son, Young Sook; Hong, Seok Il; Kim, Young Soon; Jin Yong Jae; Lee, Tae Hee; Chung, Eun Kyung; Yi, Jae Yeun; Park, Myung Jin; Kim, Yun Young; Kang, Sin Keun

    1999-04-01

    In this study, we attempted to elucidate the mechanism involved in radiation-induced modification and changes of biological factors and physicochemical factors of tumor microenvironment and develop techniques and agents for the modification of tumor microenvironment which is favorable for efficient radio-cancer therapy based on our basic study. We established in vitro tumor invasion and angiogenesis model, elucidated the importance of MMPs activation and the MMPs/TIMPs complex in the invasive transition of tumor. Furthermore we showed the signaling pathway for MMPs induction through EGF receptor and TGF beta 1 stimulated E-M transition. We also established primary culture of human endothelial cells and tubule forming condition which is utilized for the detection of novel angiogenic factors. We also identified hypoxia induced signaling pathway and showed that GBE improved blood perfusion which may increase the effectiveness of radio-cancer therapy

  4. A study for radiation-related tumor microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Son, Young Sook; Hong, Seok Il; Kim, Young Soon; Jin Yong Jae; Lee, Tae Hee; Chung, Eun Kyung; Yi, Jae Yeun; Park, Myung Jin; Kim, Yun Young; Kang, Sin Keun

    1999-04-01

    In this study, we attempted to elucidate the mechanism involved in radiation-induced modification and changes of biological factors and physicochemical factors of tumor microenvironment and develop techniques and agents for the modification of tumor microenvironment which is favorable for efficient radio-cancer therapy based on our basic study. We established in vitro tumor invasion and angiogenesis model, elucidated the importance of MMPs activation and the MMPs/TIMPs complex in the invasive transition of tumor. Furthermore we showed the signaling pathway for MMPs induction through EGF receptor and TGF beta 1 stimulated E-M transition. We also established primary culture of human endothelial cells and tubule forming condition which is utilized for the detection of novel angiogenic factors. We also identified hypoxia induced signaling pathway and showed that GBE improved blood perfusion which may increase the effectiveness of radio-cancer therapy.

  5. Toward integrative cancer immunotherapy: targeting the tumor microenvironment.

    Science.gov (United States)

    Emens, Leisha A; Silverstein, Samuel C; Khleif, Samir; Marincola, Francesco M; Galon, Jérôme

    2012-04-10

    The development of cancer has historically been attributed to genomic alterations of normal host cells. Accordingly, the aim of most traditional cancer therapies has been to destroy the transformed cells themselves. There is now widespread appreciation that the progressive growth and metastatic spread of cancer cells requires the cooperation of normal host cells (endothelial cells, fibroblasts, other mesenchymal cells, and immune cells), both local to, and at sites distant from, the site at which malignant transformation occurs. It is the balance of these cellular interactions that both determines the natural history of the cancer, and influences its response to therapy. This active tumor-host dynamic has stimulated interest in the tumor microenvironment as a key target for both cancer diagnosis and therapy. Recent data has demonstrated both that the presence of CD8⁺ T cells within a tumor is associated with a good prognosis, and that the eradication of all malignantly transformed cells within a tumor requires that the intra-tumoral concentration of cytolytically active CD8⁺ effector T cells remain above a critical concentration until every tumor cell has been killed. These findings have stimulated two initiatives in the field of cancer immunotherapy that focus on the tumor microenvironment. The first is the development of the immune score as part of the routine diagnostic and prognostic evaluation of human cancers, and the second is the development of combinatorial immune-based therapies that reduce tumor-associated immune suppression to unleash pre-existing or therapeutically-induced tumor immunity. In support of these efforts, the Society for the Immunotherapy of Cancer (SITC) is sponsoring a workshop entitled "Focus on the Target: The Tumor Microenvironment" to be held October 24-25, 2012 in Bethesda, Maryland. This meeting should support development of the immune score, and result in a position paper highlighting opportunities for the development of

  6. Targeting the Prostate Cancer Microenvironment to Improve Therapeutic Outcomes

    Science.gov (United States)

    2013-06-01

    Pathways: Involving Microenvironment Damage Responses in Cancer Therapy Resistance. Clin Cancer Res. 18: 4019-4025.  Sun, Y ., Campisi, J., Higano, C...regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011). 45. Chien, Y . et al. Control of the senescence-associated secretory phenotype by...domain-like IL-1-converting enzyme-like inhibitory protein-long confers resistance to CD95 - induced apoptosis in hematopoietic cancer cell lines. J Immunol

  7. New approaches to image thyroid cancer cells and microenvironment

    International Nuclear Information System (INIS)

    Galli, F.; Iodice, V.; Signore, A.; Lauri, C.

    2015-01-01

    Poorly differentiated thyroid cancer (PDTC) and undifferentiated thyroid cancer (UDTC) are still life-threatening pathologies, because of the lack of well-established diagnostic and therapeutic approaches. In the past, many attempts have been made to develop radiopharmaceutical to diagnose or treat radioactive iodine (RAI)-refractory metastases or recurrences, with limited results. Indeed, it was not possible to find a specific and over expressed marker to be used as target of radiopharmaceuticals or targeted therapies. Nowadays, with novel advances in the field of tumor microenvironment, many new markers are available to be used as suitable targets for targeted therapies interfering with signalling pathways of cells involved in the mechanisms that favour tumor growth and metastatization. This opened new perspective in the use of radiopharmaceuticals targeting components of tumor microenvironment for early diagnosis, pre-operative staging or therapy planning and follow up with targeted drugs. In the present review we present the state of novel approaches to image thyroid cancer and its microenvironment, focusing on RAI-refractory thyroid cancer as a real clinical problem to be solved.

  8. Mechanotransduction and Growth Factor Signalling to Engineer Cellular Microenvironments.

    Science.gov (United States)

    Cipitria, Amaia; Salmeron-Sanchez, Manuel

    2017-08-01

    Engineering cellular microenvironments involves biochemical factors, the extracellular matrix (ECM) and the interaction with neighbouring cells. This progress report provides a critical overview of key studies that incorporate growth factor (GF) signalling and mechanotransduction into the design of advanced microenvironments. Materials systems have been developed for surface-bound presentation of GFs, either covalently tethered or sequestered through physico-chemical affinity to the matrix, as an alternative to soluble GFs. Furthermore, some materials contain both GF and integrin binding regions and thereby enable synergistic signalling between the two. Mechanotransduction refers to the ability of the cells to sense physical properties of the ECM and to transduce them into biochemical signals. Various aspects of the physics of the ECM, i.e. stiffness, geometry and ligand spacing, as well as time-dependent properties, such as matrix stiffening, degradability, viscoelasticity, surface mobility as well as spatial patterns and gradients of physical cues are discussed. To conclude, various examples illustrate the potential for cooperative signalling of growth factors and the physical properties of the microenvironment for potential applications in regenerative medicine, cancer research and drug testing. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Designing the stem cell microenvironment for guided connective tissue regeneration.

    Science.gov (United States)

    Bogdanowicz, Danielle R; Lu, Helen H

    2017-12-01

    Adult mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine because of their ability to self-renew and their capacity for multilineage differentiation and tissue regeneration. For connective tissues, such as ligaments or tendons, MSCs are vital to the modulation of the inflammatory response following acute injury while also interacting with resident fibroblasts to promote cell proliferation and matrix synthesis. To date, MSC injection for connective tissue repair has yielded mixed results in vivo, likely due to a lack of appropriate environmental cues to effectively control MSC response and promote tissue healing instead of scar formation. In healthy tissues, stem cells reside within a complex microenvironment comprising cellular, structural, and signaling cues that collectively maintain stemness and modulate tissue homeostasis. Changes to the microenvironment following injury regulate stem cell differentiation, trophic signaling, and tissue healing. Here, we focus on models of the stem cell microenvironment that are used to elucidate the mechanisms of stem cell regulation and inspire functional approaches to tissue regeneration. Recent studies in this frontier area are highlighted, focusing on how microenvironmental cues modulate MSC response following connective tissue injury and, more importantly, how this unique cell environment can be programmed for stem cell-guided tissue regeneration. © 2017 New York Academy of Sciences.

  10. Modulating the Tumor Microenvironment to Enhance Tumor Nanomedicine Delivery

    Directory of Open Access Journals (Sweden)

    Bo Zhang

    2017-12-01

    Full Text Available Nanomedicines including liposomes, micelles, and nanoparticles based on the enhanced permeability and retention (EPR effect have become the mainstream for tumor treatment owing to their superiority over conventional anticancer agents. Advanced design of nanomedicine including active targeting nanomedicine, tumor-responsive nanomedicine, and optimization of physicochemical properties to enable highly effective delivery of nanomedicine to tumors has further improved their therapeutic benefits. However, these strategies still could not conquer the delivery barriers of a tumor microenvironment such as heterogeneous blood flow, dense extracellular matrix, abundant stroma cells, and high interstitial fluid pressure, which severely impaired vascular transport of nanomedicines, hindered their effective extravasation, and impeded their interstitial transport to realize uniform distribution inside tumors. Therefore, modulation of tumor microenvironment has now emerged as an important strategy to improve nanomedicine delivery to tumors. Here, we review the existing strategies and approaches for tumor microenvironment modulation to improve tumor perfusion for helping more nanomedicines to reach the tumor site, to facilitate nanomedicine extravasation for enhancing transvascular transport, and to improve interstitial transport for optimizing the distribution of nanomedicines. These strategies may provide an avenue for the development of new combination chemotherapeutic regimens and reassessment of previously suboptimal agents.

  11. Modulating the Tumor Microenvironment to Enhance Tumor Nanomedicine Delivery

    Science.gov (United States)

    Zhang, Bo; Hu, Yu; Pang, Zhiqing

    2017-01-01

    Nanomedicines including liposomes, micelles, and nanoparticles based on the enhanced permeability and retention (EPR) effect have become the mainstream for tumor treatment owing to their superiority over conventional anticancer agents. Advanced design of nanomedicine including active targeting nanomedicine, tumor-responsive nanomedicine, and optimization of physicochemical properties to enable highly effective delivery of nanomedicine to tumors has further improved their therapeutic benefits. However, these strategies still could not conquer the delivery barriers of a tumor microenvironment such as heterogeneous blood flow, dense extracellular matrix, abundant stroma cells, and high interstitial fluid pressure, which severely impaired vascular transport of nanomedicines, hindered their effective extravasation, and impeded their interstitial transport to realize uniform distribution inside tumors. Therefore, modulation of tumor microenvironment has now emerged as an important strategy to improve nanomedicine delivery to tumors. Here, we review the existing strategies and approaches for tumor microenvironment modulation to improve tumor perfusion for helping more nanomedicines to reach the tumor site, to facilitate nanomedicine extravasation for enhancing transvascular transport, and to improve interstitial transport for optimizing the distribution of nanomedicines. These strategies may provide an avenue for the development of new combination chemotherapeutic regimens and reassessment of previously suboptimal agents. PMID:29311946

  12. [Dominant Thalamus and Aphasia].

    Science.gov (United States)

    Nakano, Akiko; Shimomura, Tatsuo

    2015-12-01

    Many studies have shown that lesions of the dominant thalamus precipitate language disorders in a similar manner to transcortical aphasias, in a phenomenon known as "thalamic aphasia." In some cases, however, aphasia may not occur or may appear transiently following thalamic lesions. Furthermore, dominant thalamic lesions can produce changes in character, as observed in patients with amnesic disorder. Previous work has explored the utility of thalamic aphasia as a discriminative feature for classification of aphasia. Although the thalamus may be involved in the function of the brainstem reticular activating system and play a role in attentional network and in memory of Papez circuit or Yakovlev circuit, the mechanism by which thalamic lesion leads to the emergence of aphasic disorders is unclear. In this review, we we survey historical and recent literature on thalamic aphasia in an attempt to understand the neural processes affected by thalamic lesions.

  13. Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an interleukin-4/STAT6 pathway.

    Science.gov (United States)

    Mariotti, Jacopo; Foley, Jason; Ryan, Kaitlyn; Buxhoeveden, Nicole; Kapoor, Veena; Amarnath, Shoba; Fowler, Daniel H

    2008-12-01

    Graft rejection has been defined as the mirror image of graft-versus-host disease, which is biologically characterized primarily as a Th1-type process. As such, we reasoned that graft rejection would represent a Th1 response amenable to Th2 modulation. Indeed, adoptive transfer of host Th1-type cells mediated rejection of fully MHC-disparate murine bone marrow allografts more effectively than host Th2-type cells. Furthermore, STAT1-deficient host T cells did not differentiate into Th1-type cells in vivo and failed to mediate rejection. We next hypothesized that donor Th2 cell allograft augmentation would prevent rejection by modulation of the host Th1/Th2 balance. In the setting of donor Th2 cell therapy, host-anti-donor allospecific T cells acquired Th2 polarity, persisted posttransplantation, and did not mediate rejection. Abrogation of rejection required donor Th2 cell IL-4 secretion and host T-cell STAT6 signaling. In conclusion, T cell-mediated marrow graft rejection primarily resembles a Th1-type process that can be abrogated by donor Th2 cell therapy that promotes engraftment through a novel mechanism whereby cytokine polarization is transferred to host T cells.

  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, 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

  15. 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

  16. Autosomal dominant cramping disease.

    Science.gov (United States)

    Ricker, K; Moxley, R T

    1990-07-01

    A family was studied in which four generations (16 of 41 members) suffered from painful recurrent muscle cramping. A clear pattern of autosomal dominant inheritance was noted. The cramping first developed during adolescence or early adulthood. Electromyographic analysis indicated a neurogenic origin. The cramps seemed to be due to dysfunction of the motor neurons. The mechanisms underlying this alteration are unclear and require further investigation.

  17. Dominant optic atrophy

    DEFF Research Database (Denmark)

    Lenaers, Guy; Hamel, Christian; Delettre, Cécile

    2012-01-01

    DEFINITION OF THE DISEASE: Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) an......) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain....

  18. Public owners will dominate

    International Nuclear Information System (INIS)

    Bakken, Stein Arne

    2003-01-01

    In ten years there will still be a dominating public ownership in the energy supply sector in Norway. Statkraft will be the big actor. Norway will then be integrated in an European power market through more cables and the power price will be lower and more stable. The market will be important, but within frames set by the politicians. This article quotes the views of two central figures in the energy sector on the energy supply industry in 2014

  19. Autosomal Dominant Polycystic Kidney Disease

    Science.gov (United States)

    ... RePORT NIH Fact Sheets Home > Autosomal Dominant Polycystic Kidney Disease Small Text Medium Text Large Text Autosomal Dominant Polycystic Kidney Disease YESTERDAY Autosomal Dominant Polycystic Kidney Disease (ADPKD) resulted ...

  20. Dominating biological networks.

    Directory of Open Access Journals (Sweden)

    Tijana Milenković

    Full Text Available Proteins are essential macromolecules of life that carry out most cellular processes. Since proteins aggregate to perform function, and since protein-protein interaction (PPI networks model these aggregations, one would expect to uncover new biology from PPI network topology. Hence, using PPI networks to predict protein function and role of protein pathways in disease has received attention. A debate remains open about whether network properties of "biologically central (BC" genes (i.e., their protein products, such as those involved in aging, cancer, infectious diseases, or signaling and drug-targeted pathways, exhibit some topological centrality compared to the rest of the proteins in the human PPI network.To help resolve this debate, we design new network-based approaches and apply them to get new insight into biological function and disease. We hypothesize that BC genes have a topologically central (TC role in the human PPI network. We propose two different concepts of topological centrality. We design a new centrality measure to capture complex wirings of proteins in the network that identifies as TC those proteins that reside in dense extended network neighborhoods. Also, we use the notion of domination and find dominating sets (DSs in the PPI network, i.e., sets of proteins such that every protein is either in the DS or is a neighbor of the DS. Clearly, a DS has a TC role, as it enables efficient communication between different network parts. We find statistically significant enrichment in BC genes of TC nodes and outperform the existing methods indicating that genes involved in key biological processes occupy topologically complex and dense regions of the network and correspond to its "spine" that connects all other network parts and can thus pass cellular signals efficiently throughout the network. To our knowledge, this is the first study that explores domination in the context of PPI networks.

  1. Molecular characterization and geological microenvironment of a microbial community inhabiting weathered receding shale cliffs.

    Science.gov (United States)

    Cockell, Charles S; Pybus, David; Olsson-Francis, Karen; Kelly, Laura; Petley, David; Rosser, Nick; Howard, Kieren; Mosselmans, Fred

    2011-01-01

    Shales play an important role in many earth system processes including coastal erosion, and they form the foundations of many engineering structures. The geobiology of the interior of pyrite-containing receding shale cliffs on the coast of northeast England was examined. The surface of the weathered shales was characterised by a thin layer of disordered authigenic iron oxyhydroxides and localised acicular, platy and aggregated gypsum, which was characterised by Raman spectroscopy, XAS and SEM. These chemical changes are likely to play an important role in causing rock weakening along fractures at the micron scale, which ultimately lead to coastal retreat at the larger scale. The surface of the shale hosts a novel, low-diversity microbial community. The bacterial community was dominated by Proteobacteria, with phylotypes closely associating with Methylocella and other members of the γ-subdivision. The second largest phylogenetic group corresponded to Nitrospira. The archaeal 16S rRNA phylotypes were dominated by a single group of sequences that matched phylotypes reported from South African gold mines and possessed ammonia monooxygenase (amoA) genes. Both the phylogenetic and the mineral data show that acidic microenvironments play an important role in shale weathering, but the shale has a higher microbial diversity than previously described pyritic acid mine drainage sites. The presence of a potentially biogeochemically active microbial population on the rock surface suggests that microorganisms may contribute to early events of shale degradation and coastal erosion.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  3. B cells play key roles in th2-type airway immune responses in mice exposed to natural airborne allergens.

    Directory of Open Access Journals (Sweden)

    Li Yin Drake

    Full Text Available Humans are frequently exposed to various airborne allergens. In addition to producing antibodies, B cells participate in immune responses via various mechanisms. The roles of B cells in allergic airway inflammation and asthma have been controversial. We examined the functional importance of B cells in a mouse model of asthma, in which mice were exposed repeatedly to common airborne allergens. Naïve wild-type BALB/c mice or B cell-deficient JH-/- mice were exposed intranasally to a cocktail of allergen extracts, including Alternaria, Aspergillus, and house dust mite, every other day for two weeks. Ovalbumin was included in the cocktail to monitor the T cell immune response. Airway inflammation, lung pathology, and airway reactivity were analyzed. The airway exposure of naïve wild type mice to airborne allergens induced robust eosinophilic airway inflammation, increased the levels of Th2 cytokines and chemokines in the lung, and increased the reactivity to inhaled methacholine. These pathological changes and immune responses were attenuated in B cell-deficient JH-/- mice. The allergen-induced expansion of CD4+ T cells was impaired in the lungs and draining lymph nodes of JH-/- mice. Furthermore, lymphocytes from JH-/- mice failed to produce Th2 cytokines in response to ovalbumin re-stimulation in vitro. Our results suggest that B cells are required for the optimal development of Th2-type immune responses and airway inflammation when exposed to common airborne allergens. The therapeutic targeting of B cells may be beneficial to treat asthma in certain patients.

  4. Th2-related immune responses by the Brucella abortus cellular antigens, malate dehydrogenase, elongation factor, and arginase.

    Science.gov (United States)

    Im, Young Bin; Shim, Soojin; Park, Woo Bin; Kim, Suk; Yoo, Han Sang

    2017-09-01

    Brucellosis is an important zoonotic disease caused by Brucella species. The disease is difficult to control due to the intracellular survival of the bacterium and the lack of precise understanding of pathogenesis. Despite of continuous researches on the pathogenesis of Brucella spp. infection, there is still question on the pathogenesis, especially earlier immune response in the bacterial infection. Malate dehydrogenase (MDH), elongation factor (Tsf), and arginase (RocF), which showed serological reactivity, were purified after gene cloning, and their immune modulating activities were then analyzed in a murine model. Cytokine production profiles were investigated by stimulating RAW 264.7 cells and naïve splenocytes with the three recombinant proteins. Also, immune responses were analyzed by ELISA and an ELIspot assay after immunizing mice with the three proteins. Only TNF-α was produced in stimulated RAW 264.7 cells, whereas Th1-related cytokines, IFN-γ and IL-2, were induced in naïve splenocytes. In contrast, Th2-type immune response was more strongly induced in antigen-secreting cells in the splenocytes obtained 28 days after immunizing mice with the three proteins, as were IgM and IgG. The induction of Th2-related antibody, IgG1, was higher than the Th1-related antibody, IgG2a, in immunized mice. These results suggest that the three proteins strongly induce Th2-type immune response in vivo, even though Th1-related cytokines were produced in vitro. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    International Nuclear Information System (INIS)

    Fukuyama, Yoshiko; Tokuhara, Daisuke; Sekine, Shinichi; Kataoka, Kosuke; Markham, Jonathan D.; Irwin, Allyson R.; Moon, Grace H.; Tokuhara, Yuka; Fujihashi, Keiko; Davydova, Julia; Yamamoto, Masato; Gilbert, Rebekah S.; Fujihashi, Kohtaro

    2012-01-01

    Highlights: ► Nasal Ad-FL effectively up-regulates APC function by CD11c + DCs in mucosal tissues. ► Nasal Ad-FL induces Notch ligand (L)-expressing CD11c + DCs. ► 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 + 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 + DCs and their roles in induction of Ag-specific Th1- and Th2-cell responses. Ad-FL activated CD11c + DCs expressed increased levels of the Notch ligand (L)-expression and specific mRNA. When CD11c + DCs from various mucosal and systemic lymphoid tissues of mice given nasal OVA plus Ad-FL were cultured with CD4 + 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-γ, IL-2 and IL-4 producing CD4 + 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 + DCs to the express Notch-ligands and these activated DCs regulate the induction of Ag-specific Th1- and Th2-type cytokine responses.

  6. Potential pathogenetic role of Th17, Th0, and Th2 cells in erosive and reticular oral lichen planus.

    Science.gov (United States)

    Piccinni, M-P; Lombardelli, L; Logiodice, F; Tesi, D; Kullolli, O; Biagiotti, R; Giudizi, Mg; Romagnani, S; Maggi, E; Ficarra, G

    2014-03-01

    The role of Th17 cells and associated cytokines was investigated in oral lichen planus. 14 consecutive patients with oral lichen planus were investigated. For biological studies, tissues were taken from reticular or erosive lesions and from normal oral mucosa (controls) of the same patient. mRNA expression for IL-17F, IL-17A, MCP-1, IL-13, IL-2, IL-10, IL-1β, RANTES, IL-4, IL-12B, IL-8, IFN-γ, TNF-α, IL-1α, IL-18, TGF-β1, IL-23R, IL-7, IL-15, IL-6, MIG, IP-10, LTB, VEGF, IL-5, IL-27, IL-23A, GAPDH, PPIB, Foxp3, GATA3, and RORC was measured using the QuantiGene 2.0. Results showed that Th17-type and Th0-type molecules' mRNAs, when compared with results obtained from tissue controls, were increased in biopsies of erosive lesions, whereas Th2-type molecules' mRNAs were increased in reticular lesions. When the CD4+ T-cell clones, derived from oral lichen planus tissues and tissue controls, were analyzed, a higher prevalence of Th17 (confirmed by an increased CD161 expression) and Th0 CD4+ T clones was found in erosive lesions, whereas a prevalence of Th2 clones was observed in reticular lesions. Our data suggest that Th17, Th0, and Th2 cells, respectively, may have a role in the pathogenesis of erosive and reticular oral lichen planus. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. 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.

  8. Signals involved in the early TH1/TH2 polarization of an immune response depending on the type of antigen.

    Science.gov (United States)

    Bellinghausen, I; Brand, U; Enk, A H; Knop, J; Saloga, J

    1999-02-01

    The early production of distinct cytokines by epidermal cells (ECs) in response to antigen exposure may govern the development of TH1 -like immune responses, such as contact sensitivity, or TH2 -like immune responses, such as IgE-dependent allergies of the immediate type, depending on the type of antigen. The aim of this study was to compare the signals induced by protein allergens with those induced by haptens in ECs and subsequently in local draining lymph node cells (LNCs) or splenocytes. BALB/c mice were primed in vivo with the protein allergens ovalbumin or birch pollen or the haptens 2, 4-dinitrofluorobenzene or trinitrochlorbenzene, respectively, and cytokine and immunoglobulin secretions of responding splenocytes were measured by ELISA after in vitro coculture with ECs. Induction of cytokine mRNA expression in ECs and LNCs was analyzed by reverse transcriptase-PCR. In the presence of protein allergens, ECs enhance the induction of a TH2 immune response (IL-4 and IgE production of splenocytes), whereas a TH1 immune response (IFN-gamma and IgG2a production) was only induced in the context of haptens. Heat inactivation of ovalbumin did not diminish the development of a TH2 immune response. One direct effect of antigen on ECs was the earlier expression of IL-10 mRNA after stimulation with protein allergens (30 minutes) than with haptens (2 hours) in vitro. By using an in vivo approach, sensitization of the skin with trinitrochlorbenzene, but not with ovalbumin, resulted in an early induction of IL-1beta, IL-12p40, and IFN-gamma mRNA in LNCs, whereas IL-18 was induced by both. These data indicate that the type of antigen strongly influences the type of immune response by eliciting distinct signals already in the epithelium.

  9. 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

  10. On dominator colorings in graphs

    Indian Academy of Sciences (India)

    A dominator coloring of a graph is a proper coloring of in which every vertex dominates every vertex of at least one color class. The minimum number of colors required for a dominator coloring of is called the dominator chromatic number of and is denoted by d ( G ) . In this paper we present several results on ...

  11. Tumor microenvironment in invasive lobular carcinoma: possible therapeutic targets.

    Science.gov (United States)

    Nakagawa, Saki; Miki, Yasuhiro; Miyashita, Minoru; Hata, Shuko; Takahashi, Yayoi; Rai, Yoshiaki; Sagara, Yasuaki; Ohi, Yasuyo; Hirakawa, Hisashi; Tamaki, Kentaro; Ishida, Takanori; Watanabe, Mika; Suzuki, Takashi; Ohuchi, Noriaki; Sasano, Hironobu

    2016-01-01

    Invasive ductal and lobular carcinomas (IDC and ILC) are the two most common histological types of breast cancer, and have been considered to develop from terminal duct lobular unit but their molecular, pathological, and clinical features are markedly different between them. These differences could be due to different mechanisms of carcinogenesis and tumor microenvironment, especially cancer-associated fibroblasts (CAFs) but little has been explored in this aspect. Therefore, in this study, we evaluated the status of angiogenesis, maturation of intratumoral microvessels, and proliferation of CAFs using immunohistochemistry and PCR array analysis to explore the differences of tumor microenvironment between ILC and IDC. We studied grade- and age-matched, luminal-like ILC and IDC. We immunolocalized CD34 and αSMA for an evaluation of CAFs and CD31, Vasohibin-1, a specific marker of proliferative endothelial cells and nestin, a marker of pericytes for studying the status of proliferation and maturation of intratumoral microvessel. We also performed PCR array analysis to evaluate angiogenic factors in tumor stromal components. The number of CAFs, microvessel density, and vasohibin-1/CD31 positive ratio were all significantly higher in ILC than IDC but nestin immunoreactivity in intratumoral microvessel was significantly lower in ILC. These results did indicate that proliferation of CAFs and endothelial cells was more pronounced in ILC than IDC but newly formed microvessels were less mature than those in IDC. PCR array analysis also revealed that IGF-1 expression was higher in ILC than IDC. This is the first study to demonstrate the differences of tumor microenvironment including CAFs and proliferation and maturation of intratumoral vessels between ILC and IDC.

  12. Effect of Interleukin 1b on rat thymus microenvironment

    Directory of Open Access Journals (Sweden)

    M Artico

    2009-12-01

    Full Text Available The effect of interleukin 1b on the thymus of control and chemically sympathectomized adult and aged rats was studied with the aim of assessing the importance of adrenergic nerve fibres (ANF in the regulation of some immunological functions.The whole thymus was removed from normal, sympathectomized (with the neurotoxin 6-OH-dopamine and treated (interleukin 1b rats. Thymic slices were stained with eosin orange (for the recognition of microanatomical details of the thymic microenvironment and with Bodian’s method for staining of nerve fibres. Histofluorescence microscopy was employed for staining ANF and immunofluorescence was used for detecting NPY-like immunoreactivity. All images were submitted to quantitative morphometrical analysis and statistical analysis of data. Moreover, the amount of proteins and noradrenaline was measured on thymic homogenates. The results indicate that in normal conditions the formation of the thymic nerve plexi in the rat is complex: the majority of ANF are destroyed after chemical sympathectomy with 6-OH-dopamine and do not change after treatment with interleukin 1b; on the contrary, treatment with interleukin 1b induces substantial changes in the fresh weight of the thymus, the thymic microenvironment, thymic nerve fibers, ANF, NPY-like positive nerve fibres, and on the total amount of proteins and noradrenaline in rat thymic tissue homogenates.Immunostimulation with interleukin 1b induces substantial changes in the whole thymus, in its microenvironment and in ANF and NPY-like nerve fibres. After chemical sympathectomy, no significant immune response was evoked by interleukin 1b, since the majority of ANF was destroyed by chemical sympathectomy.

  13. Local iron homeostasis in the breast ductal carcinoma microenvironment

    International Nuclear Information System (INIS)

    Marques, Oriana; Porto, Graça; Rêma, Alexandra; Faria, Fátima; Cruz Paula, Arnaud; Gomez-Lazaro, Maria; Silva, Paula; Martins da Silva, Berta; Lopes, Carlos

    2016-01-01

    While the deregulation of iron homeostasis in breast epithelial cells is acknowledged, iron-related alterations in stromal inflammatory cells from the tumor microenvironment have not been explored. Immunohistochemistry for hepcidin, ferroportin 1 (FPN1), transferrin receptor 1 (TFR1) and ferritin (FT) was performed in primary breast tissues and axillary lymph nodes in order to dissect the iron-profiles of epithelial cells, lymphocytes and macrophages. Furthermore, breast carcinoma core biopsies frozen in optimum cutting temperature (OCT) compound were subjected to imaging flow cytometry to confirm FPN1 expression in the cell types previously evaluated and determine its cellular localization. We confirm previous results by showing that breast cancer epithelial cells present an ‘iron-utilization phenotype’ with an increased expression of hepcidin and TFR1, and decreased expression of FT. On the other hand, lymphocytes and macrophages infiltrating primary tumors and from metastized lymph nodes display an ‘iron-donor’ phenotype, with increased expression of FPN1 and FT, concomitant with an activation profile reflected by a higher expression of TFR1 and hepcidin. A higher percentage of breast carcinomas, compared to control mastectomy samples, present iron accumulation in stromal inflammatory cells, suggesting that these cells may constitute an effective tissue iron reservoir. Additionally, not only the deregulated expression of iron-related proteins in epithelial cells, but also on lymphocytes and macrophages, are associated with clinicopathological markers of breast cancer poor prognosis, such as negative hormone receptor status and tumor size. The present results reinforce the importance of analyzing the tumor microenvironment in breast cancer, extending the contribution of immune cells to local iron homeostasis in the tumor microenvironment context

  14. Bone marker gene expression in calvarial bones: different bone microenvironments.

    Science.gov (United States)

    Al-Amer, Osama

    2017-12-01

    In calvarial mice, mesenchymal stem cells (MSCs) differentiate into osteoprogenitor cells and then differentiate into osteoblasts that differentiate into osteocytes, which become embedded within the bone matrix. In this case, the cells participating in bone formation include MSCs, osteoprogenitor cells, osteoblasts and osteocytes. The calvariae of C57BL/KaLwRijHsD mice consist of the following five bones: two frontal bones, two parietal bones and one interparietal bone. This study aimed to analyse some bone marker genes and bone related genes to determine whether these calvarial bones have different bone microenvironments. C57BL/KaLwRijHsD calvariae were carefully excised from five male mice that were 4-6 weeks of age. Frontal, parietal, and interparietal bones were dissected to determine the bone microenvironment in calvariae. Haematoxylin and eosin staining was used to determine the morphology of different calvarial bones under microscopy. TaqMan was used to analyse the relative expression of Runx2, OC, OSX, RANK, RANKL, OPG, N-cadherin, E-cadherin, FGF2 and FGFR1 genes in different parts of the calvariae. Histological analysis demonstrated different bone marrow (BM) areas between the different parts of the calvariae. The data show that parietal bones have the smallest BM area compared to frontal and interparietal bones. TaqMan data show a significant increase in the expression level of Runx2, OC, OSX, RANKL, OPG, FGF2 and FGFR1 genes in the parietal bones compared with the frontal and interparietal bones of calvariae. This study provides evidence that different calvarial bones, frontal, parietal and interparietal, contain different bone microenvironments.

  15. Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment

    Science.gov (United States)

    Costa, Fabricio F; Seftor, Elisabeth A; Bischof, Jared M; Kirschmann, Dawn A; Strizzi, Luigi; Arndt, Kelly; de Fatima Bonaldo, Maria; Soares, Marcelo B; Hendrix, Mary JC

    2010-01-01

    We have previously shown that the microenvironment of human embryonic stem cells (hESCs) is able to change and reprogram aggressive cancer cells to a less aggressive state. Some mechanisms implicated in the phenotypic changes observed after this exposure are mainly associated with the Nodal signaling pathway, which plays a key role in tumor cell plasticity. However, several other molecular mechanisms might be related directly and/or indirectly to these changes, including microRNA (miRNA) regulation and DNA methylation. Aim: To further explore the epigenetic mechanisms potentially underlying the phenotypic changes that occur after exposing metastatic melanoma cells to a hESC microenvironment. Materials & Methods: A total of 365 miRNAs were screened using the TaqMan® Low Density Arrays. We also evaluated whether DNA methylation could be one of the factors regulating the expression of the inhibitor of Nodal, Lefty, in hESCs (where it is highly expressed) vs melanoma cells (where it is not expressed). Results: Using these experimental approaches, we identified miRNAs that are up- and down-regulated in melanoma cells exposed to a hESC microenvironment, such as miR-302a and miR-27b, respectively. We also demonstrate that Notch4 is one of the targets of miR-302a, which is upstream of Nodal. Additionally, one of the mechanisms that might explain the absence of the inhibitor of Nodal, Lefty, in cancer cells is silencing by DNA methylation, which provides new insights into the unregulated expression of Nodal in melanoma. Conclusion: These findings suggest that epigenetic changes such as DNA methylation and regulation by microRNAs might play a significant role in tumor cell plasticity and the metastatic phenotype. PMID:20495621

  16. Granulocyte colony-stimulating factor decreases the Th1/Th2 ratio in peripheral blood mononuclear cells from patients with chronic immune thrombocytopenic purpura in vitro.

    Science.gov (United States)

    Ge, Fei; Zhang, Zhuo; Hou, Jinxiao; Cao, Fenglin; Zhang, Yingmei; Wang, Ping; Wei, Hong; Zhou, Jin

    2016-12-01

    Chronic immune thrombocytopenia purpura (ITP) is an autoimmune disease that exhibits an abnormally high Th1/Th2 ratio. Granulocyte colony-stimulating factor (G-CSF) has been shown to decrease the Th1/Th2 ratio in healthy donors. In this study, we investigated the effects of G-CSF treatment on the Th1/Th2 cells and the underlying mechanisms in patients with ITP in vitro. Peripheral blood mononuclear cells (PBMCs) isolated from patients with ITP and healthy controls were treated with G-CSF. Expression levels of interferon (IFN)-γ, interleukin (IL)-2, IL-4, and IL-13 in supernatants were measured by enzyme-linked immunosorbent assays. The expression of IFN-γ, IL-4, and G-CSF receptor (G-CSFR) on Th1 and Th2 cells were examined by flow cytometry and confocal microscopy. The mRNA expression of IFN-γ, IL-2, IL-4, IL-13, and T-box expressed in T cells (T-bet) and GATA-binding protein 3 (GATA-3) in PBMCs was evaluated by reverse transcription polymerase chain reaction. The results showed that G-CSF could significantly reduce the Th1/Th2 ratio in PBMCs from patients with ITP in vitro. As the concentration of G-CSF increased, Th1/Th2 ([IFN-γ+IL-2]/[IL-4+IL-13]) cytokine ratios and T-bet/GATA-3 mRNA ratios decreased in a concentration-dependent manner. Th1 cells and Th2 cells both expressed G-CSFR. These results suggest that G-CSF could decrease the Th1/Th2 ratio in the context of ITP, and elucidate the direct and indirect immunomodulatory mechanisms underlying G-CSF functions in Th1/Th2 cells, thus supporting the therapeutic potential of G-CSF in the treatment of patients with ITP. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Low Dose IR Creates an Oncogenic Microenvironment by Inducing Premature

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Zhi-Min [Harvard School of Public Health

    2013-04-28

    Introduction Much of the work addressing ionizing radiation-induced cellular response has been carried out mainly with the traditional cell culture technique involving only one cell type, how cellular response to IR is influenced by the tissue microenvironment remains elusive. By use of a three-dimensional (3D) co-culture system to model critical interactions of different cell types with their neighbors and with their environment, we recently showed that low-dose IR-induced extracellular signaling via the tissue environment affects profoundly cellular responses. This proposal aims at determining the response of mammary epithelial cells in a tissue-like setting.

  18. Cancer Stem Cells and Their Microenvironment: Biology and Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Eunice Yuen-Ting Lau

    2017-01-01

    Full Text Available Tumor consists of heterogeneous cancer cells including cancer stem cells (CSCs that can terminally differentiate into tumor bulk. Normal stem cells in normal organs regulate self-renewal within a stem cell niche. Likewise, accumulating evidence has also suggested that CSCs are maintained extrinsically within the tumor microenvironment, which includes both cellular and physical factors. Here, we review the significance of stromal cells, immune cells, extracellular matrix, tumor stiffness, and hypoxia in regulation of CSC plasticity and therapeutic resistance. With a better understanding of how CSC interacts with its niche, we are able to identify potential therapeutic targets for the development of more effective treatments against cancer.

  19. Combined Effects of Pericytes in the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Aline Lopes Ribeiro

    2015-01-01

    Full Text Available Pericytes are multipotent perivascular cells whose involvement in vasculature development is well established. Evidences in the literature also suggest that pericytes display immune properties and that these cells may serve as an in vivo reservoir of stem cells, contributing to the regeneration of diverse tissues. Pericytes are also capable of tumor homing and are important cellular components of the tumor microenvironment (TME. In this review, we highlight the contribution of pericytes to some classical hallmarks of cancer, namely, tumor angiogenesis, growth, metastasis, and evasion of immune destruction, and discuss how collectively these hallmarks could be tackled by therapies targeting pericytes, providing a rationale for cancer drugs aiming at the TME.

  20. Cigarette smoking enhances T cell activation and a Th2 immune response; an aspect of the pathophysiology in periodontal disease.

    Science.gov (United States)

    de Heens, G L Torres; van der Velden, U; Loos, B G

    2009-09-01

    Smoking is a strong risk factor for periodontitis. Treated patients who smoke show increased risk for further periodontal breakdown, despite receiving maintenance care. Previous work indicated that such patients have a monocytic cytokine response favoring Th2 activity. The purpose of this study was to investigate the T lymphocytic cytokine production representing Th1 and Th2 subpopulations in smokers and non-smokers. Venous blood was collected from 30 treated periodontitis patients (12 smokers) and 24 healthy subjects (12 smokers). Whole blood cell cultures were stimulated and interferon (IFN)-gamma and interleukin (IL)-13 were measured in the culture supernatants, representing types 1 and 2 Th subpopulations, respectively. Unadjusted data showed that smokers had more lymphocytes, and higher levels of IFN-gamma and IL-13, irrespective of being periodontal patient. However in a multivariate analysis, increased IFN-gamma production was not significantly explained by smoking, while higher IL-13 was strongly explained by smoking (21%, psmoking patients which may induce conversion of periodontal stability into progressive disease. This phenomenon may be equally important in other conditions, where connective tissue and bone loss are hallmarks of disease pathophysiology.

  1. Hypoxia alters the physical properties of the tumor microenvironment

    Science.gov (United States)

    Gilkes, Daniele

    Of all the deaths attributed to cancer, 90% are due to metastasis, or the spread of cancer cells from a primary tumor to distant organs, and treatments that prevent or cure metastasis remain elusive. Emerging data indicate that low oxygen states within a tumor, termed hypoxia, can alter the chemical and physical parameters of the extracellular matrix (ECM), or scaffold of the tumor tissue. These changes generate a microenvironment that may be more conducive for promoting metastasis. During tumor evolution, changes in the composition and the overall content of the ECM reflect both its biophysical and biological properties and these strongly influence the cells properties, such as cellular proliferation and cell motility. The talk will cover how hypoxia arises within normal tissue and also in tumors. We will cover the role of hypoxia in collagen biogenesis which influences compositional changes to the tumor microenvironment and discuss how these changes lead to a stiffer tumor stroma. The challenges in determining the influence of chemical versus physical cues on cancer progression will also be considered.

  2. Pulmonary emphysema and tumor microenvironment in primary lung cancer.

    Science.gov (United States)

    Murakami, Junichi; Ueda, Kazuhiro; Sano, Fumiho; Hayashi, Masataro; Nishimoto, Arata; Hamano, Kimikazu

    2016-02-01

    To clarify the relationship between the presence of pulmonary emphysema and tumor microenvironment and their significance for the clinicopathologic aggressiveness of non-small cell lung cancer. The subjects included 48 patients with completely resected and pathologically confirmed stage I non-small cell lung cancer. Quantitative computed tomography was used to diagnose pulmonary emphysema, and immunohistochemical staining was performed to evaluate the matrix metalloproteinase (MMP) expression status in the intratumoral stromal cells as well as the microvessel density (MVD). Positive MMP-9 staining in the intratumoral stromal cells was confirmed in 17 (35%) of the 48 tumors. These 17 tumors were associated with a high MVD, frequent lymphovascular invasion, a high proliferative activity, and high postoperative recurrence rate (all, P pulmonary emphysema (P = 0.02). Lung cancers arising from pulmonary emphysema were also associated with a high MVD, proliferative activity, and postoperative recurrence rate (all, P < 0.05). The MMP-9 expression in intratumoral stromal cells is associated with the clinicopathologic aggressiveness of lung cancer and is predominantly identified in tumors arising in emphysematous lungs. Further studies regarding the biological links between the intratumoral and extratumoral microenvironment will help to explain why lung cancers originating in emphysematous lung tissues are associated with a poor prognosis. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Stroma Cells in Tumor Microenvironment and Breast Cancer

    Science.gov (United States)

    Mao, Yan; Keller, Evan T.; Garfield, David H.; Shen, Kunwei; Wang, Jianhua

    2015-01-01

    Cancer is a systemic disease, encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion and metastasis. In breast cancer, CAFs not only promote tumor progression, but also induce therapeutic resistances. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistances. This review summarizes the current understanding of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. The effects of other stromal components such as endothelial cells, macrophages and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to sort patients into a specific and confirmed subtype for personalized treatment. PMID:23114846

  4. Absorbed dose in fibrotic microenvironment models employing Monte Carlo simulation

    International Nuclear Information System (INIS)

    Zambrano Ramírez, O.D.; Rojas Calderón, E.L.; Azorín Vega, E.P.; Ferro Flores, G.; Martínez Caballero, E.

    2015-01-01

    The presence or absence of fibrosis and yet more, the multimeric and multivalent nature of the radiopharmaceutical have recently been reported to have an effect on the radiation absorbed dose in tumor microenvironment models. Fibroblast and myofibroblast cells produce the extracellular matrix by the secretion of proteins which provide structural and biochemical support to cells. The reactive and reparative mechanisms triggered during the inflammatory process causes the production and deposition of extracellular matrix proteins, the abnormal excessive growth of the connective tissue leads to fibrosis. In this work, microenvironment (either not fibrotic or fibrotic) models composed of seven spheres representing cancer cells of 10 μm in diameter each with a 5 μm diameter inner sphere (cell nucleus) were created in two distinct radiation transport codes (PENELOPE and MCNP). The purpose of creating these models was to determine the radiation absorbed dose in the nucleus of cancer cells, based on previously reported radiopharmaceutical retain (by HeLa cells) percentages of the 177 Lu-Tyr 3 -octreotate (monomeric) and 177 Lu-Tyr 3 -octreotate-AuNP (multimeric) radiopharmaceuticals. A comparison in the results between the PENELOPE and MCNP was done. We found a good agreement in the results of the codes. The percent difference between the increase percentages of the absorbed dose in the not fibrotic model with respect to the fibrotic model of the codes PENELOPE and MCNP was found to be under 1% for both radiopharmaceuticals. (authors)

  5. Impact craters as biospheric microenvironments, Lawn Hill Structure, Northern Australia.

    Science.gov (United States)

    Lindsay, John; Brasier, Martin

    2006-04-01

    Impact craters on Mars act as traps for eolian sediment and in the past may have provided suitable microenvironments that could have supported and preserved a stressed biosphere. If this is so, terrestrial impact structures such as the 18-km-diameter Lawn Hill Structure, in northern Australia, may prove useful as martian analogs. We sampled outcrop and drill core from the carbonate fill of the Lawn Hill Structure and recorded its gamma-log signature. Facies data along with whole rock geochemistry and stable isotope signatures show that the crater fill is an outlier of the Georgina Basin and was formed by impact at, or shortly before, approximately 509-506 million years ago. Subsequently, it was rapidly engulfed by the Middle Cambrian marine transgression, which filled it with shallow marine carbonates and evaporites. The crater formed a protected but restricted microenvironment in which sediments four times the thickness of the nearby basinal succession accumulated. Similar structures, common on the martian surface, may well have acted as biospheric refuges as the planet's water resources declined. Low-pH aqueous environments on Earth similar to those on Mars, while extreme, support diverse ecologies. The architecture of the eolian crater fill would have been defined by long-term ground water cycles resulting from intermittent precipitation in an extremely arid climate. Nutrient recycling, critical to a closed lacustrine sub-ice biosphere, could be provided by eolian transport onto the frozen water surface.

  6. Inflammatory Alterations of the Extracellular Matrix in the Tumor Microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Iijima, Junko [Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-Ku, Kyoto 603-8555 (Japan); Konno, Kenjiro [Department of Animal Medical Sciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-Ku, Kyoto 603-8555 (Japan); Itano, Naoki, E-mail: itanon@cc.kyoto-su.ac.jp [Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-Ku, Kyoto 603-8555 (Japan)

    2011-08-09

    Complex interactions between cancer cells and host stromal cells result in the formation of the “tumor microenvironment”, where inflammatory alterations involve the infiltration of tumor-associated fibroblasts and inflammatory leukocytes that contribute to the acquisition of malignant characteristics, such as increased cancer cell proliferation, invasiveness, metastasis, angiogenesis, and avoidance of adaptive immunity. The microenvironment of a solid tumor is comprised not only of cellular compartments, but also of bioactive substances, including cytokines, growth factors, and extracellular matrix (ECM). ECM can act as a scaffold for cell migration, a reservoir for cytokines and growth factors, and a signal through receptor binding. During inflammation, ECM components and their degraded fragments act directly and indirectly as inflammatory stimuli in certain cases and regulate the functions of inflammatory and immune cells. One such ECM component, hyaluronan, has recently been implicated to modulate innate immune cell function through pattern recognition toll-like receptors and accelerate the recruitment and activation of tumor-associated macrophages in inflamed cancers. Here, we will summarize the molecular mechanism linking inflammation with ECM remodeling in the tumor microenvironment, with a particular emphasis on the role of hyaluronan in controlling the inflammatory response.

  7. Inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma.

    Science.gov (United States)

    Han, Ke-Qi; He, Xue-Qun; Ma, Meng-Yu; Guo, Xiao-Dong; Zhang, Xue-Min; Chen, Jie; Han, Hui; Zhang, Wei-Wei; Zhu, Quan-Gang; Nian, Hua; Ma, Li-Jun

    2015-04-28

    To study the inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma (HCC) in nude mice. CBRH-7919 HCC cells were injected into the subcutaneous region of nude mice. Beginning two weeks after the challenge, tumor growth was measured every week for six weeks. The stromal microenvironment and inflammatory cell infiltration was assessed by immunohistochemistry in paired tumor and adjacent peritumoral samples, and macrophage phenotype was assessed using double-stain immunohistochemistry incorporating expression of an intracellular enzyme. A chemokine PCR array, comprised of 98 genes, was used to screen differential gene expressions, which were validated by Western blotting. Additionally, expression of identified chemokines was knocked-down by RNA interference, and the effect on tumor growth was assessed. Inflammatory cell infiltrates are a key feature of adjacent peritumoral tissues with increased macrophage, neutrophil, and T cell (specifically helper and activated subsets) infiltration. Macrophages within adjacent peritumoral tissues express inducible nitric oxide synthase, suggestive of a proinflammatory phenotype. Fifty-one genes were identified in tumor tissues during the progression period, including 50 that were overexpressed (including CXCL1, CXCL2 and CXCL3) and three that were underexpressed (CXCR1, Ifg and Actb). RNA interference of CXCL1 in the CBRH-7919 cells decreased the growth of tumors in nude mice and inhibited expression of CXCL2, CXCL3 and interleukin-1β protein. These findings suggest that CXCL1 plays a critical role in tumor growth and may serve as a potential molecular target for use in HCC therapy.

  8. Oxidative and Nitrosative Stress in the Metastatic Microenvironment

    International Nuclear Information System (INIS)

    Ortega, Ángel L.; Mena, Salvador; Estrela, José M.

    2010-01-01

    Metastases that are resistant to conventional therapies are the main cause of most cancer-related deaths in humans. Tumor cell heterogeneity, which associates with genomic and phenotypic instability, represents a major problem for cancer therapy. Additional factors, such as the attack of immune cells or organ-specific microenvironments, also influence metastatic cell behavior and the response to therapy. Interaction of cancer and endothelial cells in capillary beds, involving mechanical contact and transient adhesion, is a critical step in the initiation of metastasis. This interaction initiates a cascade of activation pathways that involves cytokines, growth factors, bioactive lipids and reactive oxygen and nitrogen species (ROS and RNS) produced by either the cancer cell or the endothelium. Vascular endothelium-derived NO and H 2 O 2 are cytotoxic for the cancer cells, but also help to identify some critical molecular targets that appear essential for survival of invasive metastatic cell subsets. Surviving cancer cells that extravasate and start colonization of an organ or tissue can still be attacked by macrophages and be influenced by specific intraorgan microenvironment conditions. At all steps; from the primary tumor until colonization of a distant organ; metastatic cells undergo a dynamic process of constant adaptations that may lead to the survival of highly resistant malignant cell subsets. In this sequence of molecular events both ROS and RNS play key roles

  9. Oxidative and Nitrosative Stress in the Metastatic Microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Ortega, Ángel L. [Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 15 Av. Blasco Ibañez, 46010 Valencia (Spain); Mena, Salvador [Green Molecular S.L., Pol. Ind. La Coma-Parc Cientific, 46190 Paterna, Valencia (Spain); Estrela, José M., E-mail: jose.m.estrela@uv.es [Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 15 Av. Blasco Ibañez, 46010 Valencia (Spain)

    2010-03-26

    Metastases that are resistant to conventional therapies are the main cause of most cancer-related deaths in humans. Tumor cell heterogeneity, which associates with genomic and phenotypic instability, represents a major problem for cancer therapy. Additional factors, such as the attack of immune cells or organ-specific microenvironments, also influence metastatic cell behavior and the response to therapy. Interaction of cancer and endothelial cells in capillary beds, involving mechanical contact and transient adhesion, is a critical step in the initiation of metastasis. This interaction initiates a cascade of activation pathways that involves cytokines, growth factors, bioactive lipids and reactive oxygen and nitrogen species (ROS and RNS) produced by either the cancer cell or the endothelium. Vascular endothelium-derived NO and H{sub 2}O{sub 2} are cytotoxic for the cancer cells, but also help to identify some critical molecular targets that appear essential for survival of invasive metastatic cell subsets. Surviving cancer cells that extravasate and start colonization of an organ or tissue can still be attacked by macrophages and be influenced by specific intraorgan microenvironment conditions. At all steps; from the primary tumor until colonization of a distant organ; metastatic cells undergo a dynamic process of constant adaptations that may lead to the survival of highly resistant malignant cell subsets. In this sequence of molecular events both ROS and RNS play key roles.

  10. Multiple Myeloma Macrophages: Pivotal Players in the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Simona Berardi

    2013-01-01

    Full Text Available Tumor microenvironment is essential for multiple myeloma (MM growth, progression, and drug resistance through provision of survival signals and secretion of growth and proangiogenic factors. This paper examines the importance of macrophages within MM bone marrow (BM microenvironment, referred to as MM-associated macrophages, as a potential niche component that supports tumor plasma cells. These macrophages are derived from peripheral blood monocytes recruited into the tumor. Upon activation by MM plasma cells and mesenchymal stromal cells, macrophages can release growth factors, proteolytic enzymes, cytokines, and inflammatory mediators that promote plasma cell growth and survival. Macrophages promote tumor progression through several mechanisms including angiogenesis, growth, and drug resistance. Indeed, these macrophages are essential for the induction of an angiogenic response through vasculogenic mimicry, and this ability proceeds in step with progression of the plasma cell tumors. Data suggest that macrophages play an important role in the biology and survival of patients with MM, and they may be a target for the MM antivascular management.

  11. Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3D surrogate microenvironment.

    Science.gov (United States)

    Belloni, Daniela; Heltai, Silvia; Ponzoni, Maurilio; Villa, Antonello; Vergani, Barbara; Pecciarini, Lorenza; Marcatti, Magda; Girlanda, Stefania; Tonon, Giovanni; Ciceri, Fabio; Caligaris-Cappio, Federico; Ferrarini, Marina; Ferrero, Elisabetta

    2018-04-01

    Multiple myeloma develops primarily inside the bone marrow microenvironment, that confers pro-survival signals and drug resistance. 3D cultures that reproduce multiple myeloma-bone marrow interactions are needed to fully investigate multiple myeloma pathogenesis and response to drugs. To this purpose, we exploited the 3D Rotary Cell Culture System bioreactor technology for myeloma-bone marrow co-cultures in gelatin scaffolds. The model was validated with myeloma cell lines that, as assessed by histochemical and electron-microscopic analyses, engaged contacts with stromal cells and endothelial cells. Consistently, pro-survival signaling and also cell adhesion-mediated drug resistance were significantly higher in 3D than in 2D parallel co-cultures. The contribution of the VLA-4/VCAM1 pathway to resistance to bortezomib was modeled by the use of VCAM1 transfectants. Soluble factor-mediated drug resistance could be also demonstrated in both 2D and 3D co-cultures. The system was then successfully applied to co-cultures of primary myeloma cells-primary myeloma bone marrow stromal cells from patients and endothelial cells, allowing the development of functional myeloma-stroma interactions and MM cell long-term survival. Significantly, genomic analysis performed in a high-risk myeloma patient demonstrated that culture in bioreactor paralleled the expansion of the clone that ultimately dominated in vivo Finally, the impact of bortezomib on myeloma cells and on specialized functions of the microenvironment could be evaluated. Our findings indicate that 3D dynamic culture of reconstructed human multiple myeloma microenvironments in bioreactor may represent a useful platform for drug testing and for studying tumor-stroma molecular interactions. Copyright© 2018 Ferrata Storti Foundation.

  12. 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

    by interleukin-4 (IL-4)-producing Th2 cells, or cure may result by Th1 cells secreting gamma interferon (IFN-gamma). The present study examined the potential of human T cells to generate Th1 or Th2 responses to L. donovani. The profiles of IFN-gamma, IL-4, and lymphotoxin secretion after antigen stimulation were...... 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....

  13. Lead effects on development and function of bone marrow-derived dendritic cells promote Th2 immune responses

    International Nuclear Information System (INIS)

    Gao Donghong; Mondal, Tapan K.; Lawrence, David A.

    2007-01-01

    Although lead (Pb) has significant effects on the development and function of macrophages, B cells, and T cells and has been suggested to promote allergic asthma in mice and humans, Pb modulation of bone marrow (BM)-derived dendritic cells (DCs) and the resultant DC effects on Th1 and Th2 development have not been examined. Accordingly, we cultured BM cells with murine granulocyte macrophage-colony stimulating factor (mGM-CSF) ± PbCl 2 . At day 10, culture supernatant (SN) and non-adherent cells were harvested for analysis. Additionally, day 10 non-adherent BM-DCs were harvested and recultured with mGM-CSF + LPS ± Pb for 2 days. The day 10 Pb exposure significantly inhibited BM-DC generation, based on CD11c expression. Although fewer DCs were generated with Pb, the existing Pb-exposed DCs had significantly greater MHC-II expression than did the non-Pb-exposed DCs. However, these differences diminished upon LPS stimulation. After LPS stimulation, CD80, CD86, CD40, CD54, and MHC-II were all up-regulated on both Pb-DCs and DCs, but Pb-DCs expressed significantly less CD80 than did DCs. The CD86:CD80 ratio suggests a Pb-DC potential for Th2 cell development. After LPS stimulation, IL-6, IL-10, IL-12 (p70), and TNF-α levels significantly increased with both Pb-DCs and DCs, but Pb-DCs produced significantly less cytokines than did DCs, except for IL-10, which further supports Pb-DC preferential skewing toward type-2 immunity. In vitro studies confirm that Pb-DCs have the ability to polarize antigen-specific T cells to Th2 cells. Pb-DCs also enhanced allogeneic and autologous T cell proliferation in vitro, and in vivo studies suggested that Pb-DCs inhibited Th1 effects on humoral and cell-mediated immunity. The Pb effect was mainly on DCs, rather than on T cells, and Pb's modification of DC function appears to be the main cause of Pb's promotion of type-2-related immunity, which may relate to Pb's enhanced activation of the Erk/MAP kinase pathway

  14. Human leukocyte antigen-G expression in differentiated human airway epithelial cells: lack of modulation by Th2-associated cytokines

    Directory of Open Access Journals (Sweden)

    White Steven R

    2013-01-01

    Full Text Available Abstract Background Human leukocyte antigen (HLA-G is a nonclassical class I antigen with immunomodulatory roles including up-regulation of suppressor T regulatory lymphocytes. HLA-G was recently identified as an asthma susceptibility gene, and expression of a soluble isoform, HLA-G5, has been demonstrated in human airway epithelium. Increased presence of HLA-G5 has been demonstrated in bronchoalveolar lavage fluid recovered from patients with mild asthma; this suggests a role for this isoform in modulating airway inflammation though the mechanisms by which this occurs is unclear. Airway inflammation associated with Th2 cytokines such as IL-4 and IL-13 is a principal feature of asthma, but whether these cytokines elicit expression of HLA-G is not known. Methods We examined gene and protein expression of both soluble (G5 and membrane-bound (G1 HLA-G isoforms in primary differentiated human airway epithelial cells collected from normal lungs and grown in air-liquid interface culture. Cells were treated with up to 10 ng/ml of either IL-4, IL-5, or IL-13, or 100 ng/ml of the immunomodulatory cytokine IL-10, or 10,000 U/ml of the Th1-associated cytokine interferon-beta, for 24 hr, after which RNA was isolated for evaluation by quantitative PCR and protein was collected for Western blot analysis. Results HLA-G5 but not G1 was present in dAEC as demonstrated by quantitative PCR, western blot and confocal microscopy. Neither G5 nor G1 expression was increased by the Th2-associated cytokines IL-4, IL-5 or IL-13 over 24 hr, nor after treatment with IL-10, but was increased 4.5 ± 1.4 fold after treatment with 10,000 U/ml interferon-beta. Conclusions These data demonstrate the constitutive expression of a T lymphocyte regulatory molecule in differentiated human airway epithelial cells that is not modulated by Th2-associated cytokines.

  15. The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer

    Science.gov (United States)

    Senthebane, Dimakatso Alice; Rowe, Arielle; Shipanga, Hendrina; Munro, Daniella; Al Mazeedi, Mohammad A. M.; Almazyadi, Hashim A. M.; Kallmeyer, Karlien

    2017-01-01

    Chemoresistance is a leading cause of morbidity and mortality in cancer and it continues to be a challenge in cancer treatment. Chemoresistance is influenced by genetic and epigenetic alterations which affect drug uptake, metabolism and export of drugs at the cellular levels. While most research has focused on tumor cell autonomous mechanisms of chemoresistance, the tumor microenvironment has emerged as a key player in the development of chemoresistance and in malignant progression, thereby influencing the development of novel therapies in clinical oncology. It is not surprising that the study of the tumor microenvironment is now considered to be as important as the study of tumor cells. Recent advances in technological and analytical methods, especially ‘omics’ technologies, has made it possible to identify specific targets in tumor cells and within the tumor microenvironment to eradicate cancer. Tumors need constant support from previously ‘unsupportive’ microenvironments. Novel therapeutic strategies that inhibit such microenvironmental support to tumor cells would reduce chemoresistance and tumor relapse. Such strategies can target stromal cells, proteins released by stromal cells and non-cellular components such as the extracellular matrix (ECM) within the tumor microenvironment. Novel in vitro tumor biology models that recapitulate the in vivo tumor microenvironment such as multicellular tumor spheroids, biomimetic scaffolds and tumor organoids are being developed and are increasing our understanding of cancer cell-microenvironment interactions. This review offers an analysis of recent developments on the role of the tumor microenvironment in the development of chemoresistance and the strategies to overcome microenvironment-mediated chemoresistance. We propose a systematic analysis of the relationship between tumor cells and their respective tumor microenvironments and our data show that, to survive, cancer cells interact closely with tumor

  16. On dominator colorings in graphs

    Indian Academy of Sciences (India)

    A dominator coloring of a graph G is a proper coloring of G in which every vertex dominates every vertex of at least one color class. The minimum number of colors required for a dominator coloring of G is called the dominator chromatic number of G and is denoted by χd(G). In this paper we present several results on graphs ...

  17. Electronic structure and thermoelectric transport properties of the golden Th2S3-type Ti2O3 under pressure

    Directory of Open Access Journals (Sweden)

    Bin Xu

    2016-05-01

    Full Text Available A lot of physical properties of Th2S3-type Ti2O3 have investigated experimentally, hence, we calculated electronic structure and thermoelectric transport properties by the first-principles calculation under pressure. The increase of the band gaps is very fast from 30GP to 35GP, which is mainly because of the rapid change of the lattice constants. The total density of states becomes smaller with increasing pressure, which shows that Seebeck coefficient gradually decreases. Two main peaks of Seebeck coefficients always decrease and shift to the high doping area with increasing temperature under pressure. The electrical conductivities always decrease with increasing temperature under pressure. The electrical conductivity can be improved by increasing pressure. Electronic thermal conductivity increases with increasing pressure. It is noted that the thermoelectric properties is reduced with increasing temperature.

  18. Chronic effects of exhausting exercise and overtraining on the immune response: Th1 and Th2 profile

    Directory of Open Access Journals (Sweden)

    Thiago Teixeira Guimarães

    2017-12-01

    Full Text Available Although physical inactivity figures as one of the main causes attributed to mortality, the damage caused by excessive exercise is also a reality. Professional athletes, amateur or uncompetitive modalities beneficiaries are often affected by deleterious conditions resulting from excessive exercise, such as neurological, endocrine and immune origin. The thin line between losses and benefits of successive fatiguing sessions effort depends on the understanding of concepts and methodological training principles. Exercise may have a paradoxical relationship and its consistent prescription in terms of public health depends on a better understanding of their cellular mechanisms. In this sense, the purpose of this review was to explore a promising topic in sports science, able to contribute to elucidate such mechanisms: Th1 and Th2 profile of the immune response related with chronic exhausting exercise and overtraining.

  19. Suppression of Th2 immune responses by the sulfated polysaccharide from Porphyra haitanensis in tropomyosin-sensitized mice.

    Science.gov (United States)

    Shi, Chaolan; Pan, Tzuming; Cao, Minjie; Liu, Qingmei; Zhang, Lingjing; Liu, Guangming

    2015-02-01

    The sulfated polysaccharide from Porphyra was hypothesized to exhibit immunoregulatory, anti-tumor and anti-inflammatory activity, but its anti-allergic activity is not fully understood. Therefore, the aim of this study was to isolate sulfated polysaccharide from Porphyra haitanensis (PHPS) and investigate its anti-allergic potential using a tropomyosin (TM)-induced mouse allergy model. Intraperitoneal injection of PHPS suppressed the allergic reaction by modulating serum IgE, IgG1 and IgG2a levels in mice. In particular, when PHPS was injected prior to the first immunization with TM, the IgE level decreased by 34.2% compared with the control (PBS) group. Oral therapeutic administration of PHPS to TM-sensitized mice decreased histamine release and repaired the pathology in the jejunum of the small intestine. In vitro, the mRNA expressions of the TM-induced Th2 cytokines (interleukin-4 (IL-4), IL-5 and IL-13) in splenic lymphocytes were reduced by PHPS; however, the expression of Th1 and regulatory cytokines (interferon gamma (IFN-γ) and IL-10) were up-regulated in PHPS-treated splenic lymphocytes. In the splenic lymphocyte supernatant, the IL-4, IL-13 and IFN-γ levels were also regulated by PHPS. Moreover, PHPS induced IFN-γ secretion via the Jun N-terminal kinase (JNK) and Janus kinase 2 (JAK2) signaling pathways. Therefore, these results suggest that PHPS suppresses the TM-induced allergic reaction, possibly by modulating the imbalance of the Th1/Th2 immune response. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Development and function of invariant natural killer T cells producing T(h2- and T(h17-cytokines.

    Directory of Open Access Journals (Sweden)

    Hiroshi Watarai

    2012-02-01

    Full Text Available There is heterogeneity in invariant natural killer T (iNKT cells based on the expression of CD4 and the IL-17 receptor B (IL-17RB, a receptor for IL-25 which is a key factor in T(H2 immunity. However, the development pathway and precise function of these iNKT cell subtypes remain unknown. IL-17RB⁺iNKT cells are present in the thymic CD44⁺/⁻ NK1.1⁻ population and develop normally even in the absence of IL-15, which is required for maturation and homeostasis of IL-17RB⁻iNKT cells producing IFN-γ. These results suggest that iNKT cells contain at least two subtypes, IL-17RB⁺ and IL-17RB⁻ subsets. The IL-17RB⁺iNKT subtypes can be further divided into two subtypes on the basis of CD4 expression both in the thymus and in the periphery. CD4⁺ IL-17RB⁺iNKT cells produce T(H2 (IL-13, T(H9 (IL-9 and IL-10, and T(H17 (IL-17A and IL-22 cytokines in response to IL-25 in an E4BP4-dependent fashion, whereas CD4⁻ IL-17RB⁺iNKT cells are a retinoic acid receptor-related orphan receptor (RORγt⁺ subset producing T(H17 cytokines upon stimulation with IL-23 in an E4BP4-independent fashion. These IL-17RB⁺iNKT cell subtypes are abundantly present in the lung in the steady state and mediate the pathogenesis in virus-induced airway hyperreactivity (AHR. In this study we demonstrated that the IL-17RB⁺iNKT cell subsets develop distinct from classical iNKT cell developmental stages in the thymus and play important roles in the pathogenesis of airway diseases.

  1. The effect of size-segregated ambient particulate matter on Th1/Th2-like immune responses in mice.

    Science.gov (United States)

    Huang, Kuo-Liang; Liu, Szu-Yuan; Chou, Charles C K; Lee, Yi-Hsin; Cheng, Tsun-Jen

    2017-01-01

    Particulate matter (PM) has been associated with increased pulmonary and cardiovascular mortality and morbidity. Additionally, PM is known to exacerbate asthma. However, whether ambient PM exposure contributes to the onset of asthma, especially in non-atopic children and adults, is less conclusive. The current study aimed to evaluate the effects of size-fractioned PM on lung immune responses in healthy BALB/c mice. We collected PM10, PM2.5, PM1 and PM0.1 samples from October 2012 to August 2013 in the Taipei Basin. These PM samples were representative of urban traffic pollution. The samples were extracted and sonicated in phosphate-buffered saline (PBS). Female BALB/c mice were exposed to the samples via intratracheal instillation at three different doses: 1.75 mg/kg (35 μg/per mouse), 5 mg/kg (100 μg/per mouse), and 12.5 mg/kg (250 μg/per mouse). The mice were exposed on days 0 and 7, and PBS alone was used as a control. Following the exposures, the expression profiles of inflammatory cells and cytokines in bronchoalveolar lavage fluid (BALF) were assessed. Exposure to PM10 resulted in inflammatory responses, including the recruitment of neutrophils and the induction of T helper 1 (Th1) cell-related cytokine release, such as TNF-α and IFN-γ. Furthermore, an allergic immune response, including the recruitment of eosinophils and the up-regulation of T helper 2 (Th2) cell-related cytokine release, such as IL-5 and IL-13, was also observed in the BALF of mice exposed to PM10. Our study showed that exposure to PM alone caused mixed Th1/Th2 inflammatory responses in healthy mice. These findings support the hypothesis that PM may contribute to the onset of asthma.

  2. The effect of size-segregated ambient particulate matter on Th1/Th2-like immune responses in mice.

    Directory of Open Access Journals (Sweden)

    Kuo-Liang Huang

    Full Text Available Particulate matter (PM has been associated with increased pulmonary and cardiovascular mortality and morbidity. Additionally, PM is known to exacerbate asthma. However, whether ambient PM exposure contributes to the onset of asthma, especially in non-atopic children and adults, is less conclusive. The current study aimed to evaluate the effects of size-fractioned PM on lung immune responses in healthy BALB/c mice.We collected PM10, PM2.5, PM1 and PM0.1 samples from October 2012 to August 2013 in the Taipei Basin. These PM samples were representative of urban traffic pollution. The samples were extracted and sonicated in phosphate-buffered saline (PBS. Female BALB/c mice were exposed to the samples via intratracheal instillation at three different doses: 1.75 mg/kg (35 μg/per mouse, 5 mg/kg (100 μg/per mouse, and 12.5 mg/kg (250 μg/per mouse. The mice were exposed on days 0 and 7, and PBS alone was used as a control. Following the exposures, the expression profiles of inflammatory cells and cytokines in bronchoalveolar lavage fluid (BALF were assessed. Exposure to PM10 resulted in inflammatory responses, including the recruitment of neutrophils and the induction of T helper 1 (Th1 cell-related cytokine release, such as TNF-α and IFN-γ. Furthermore, an allergic immune response, including the recruitment of eosinophils and the up-regulation of T helper 2 (Th2 cell-related cytokine release, such as IL-5 and IL-13, was also observed in the BALF of mice exposed to PM10.Our study showed that exposure to PM alone caused mixed Th1/Th2 inflammatory responses in healthy mice. These findings support the hypothesis that PM may contribute to the onset of asthma.

  3. Higher numbers of memory B-cells and Th2-cytokine skewing in high responders to hepatitis B vaccination.

    Science.gov (United States)

    Doedée, A M C M; Kannegieter, N; Öztürk, K; van Loveren, H; Janssen, R; Buisman, A M

    2016-04-27

    In the present study, differences in hepatitis B surface antigen (HBsAg)-specific memory B-cell responses between low and high responders to hepatitis B vaccine (HepB), based on levels of antibodies against HBsAg (anti-HBs), were determined. In addition, HBsAg specific T-cell responses between high (anti-HBs level >20,000 IU/L) and low (anti-HBs level cells, plasma immunoglobulin G (Ig) levels, and T-cell cytokine concentrations were measured in low and high responders directly before and one month after the second booster vaccination. In advance, an Enzyme-linked Immunosorbent Spot (ELISpot) Assay was optimized for the determination of HBsAg-specific B-cell responses. The number of HBsAg-specific B-cells was significantly higher (pvaccination with HepB. In addition, the plasma IgG levels and numbers of HBsAg-specific B-cells were significantly correlated (RS=0.66, pcell response showed the same values in the low and high responder group and did not change by the booster vaccination with HepB. However, a significant correlation (RS=0.6975, p=0.007) between the IL-13 levels and the plasma IgG levels post-booster was found. Subsequently, the IL-13 level in the high-responder group post-booster was significantly higher compared to the low-responder group. Since activation of the B-cell response after vaccination is induced by Th2 cells and IL-13 is produced by these cells, we conclude that the difference in HBsAg-specific Th2 cells is involved in determining the differences in anti-HBs level and memory B-cell numbers between low and high responders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Immunomodulatory effects of Pseudostellaria heterophylla (Miquel) Pax on regulation of Th1/Th2 levels in mice with atopic dermatitis.

    Science.gov (United States)

    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.

  5. Piper nigrum extract ameliorated allergic inflammation through inhibiting Th2/Th17 responses and mast cells activation.

    Science.gov (United States)

    Bui, Thi Tho; Piao, Chun Hua; Song, Chang Ho; Shin, Hee Soon; Shon, Dong-Hwa; Chai, Ok Hee

    2017-12-01

    Piper nigrum (Piperaceae) is commonly used as a spice and traditional medicine in many countries. P. nigrum has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the effect of P. nigrum on allergic asthma has not been known. This study investigated the effect of P. nigrum ethanol extracts (PNE) on airway inflammation in asthmatic mice model. In the ovalbumin (OVA)-induced allergic asthma model, we analysed the number of inflammatory cells and cytokines production in bronchoalveolar lavage fluid (BALF) and lung tissue; histological structure; as well as the total immunoglobulin (Ig)E, anti-OVA IgE, anti-OVA IgG 1 and histamine levels in serum. The oral administration (200 mg/kg) of PNE reduced the accumulation of inflammatory cells (eosinophils, neutrophils in BALF and mast cells in lung tissue); regulated the balance of the cytokines production of Th1, Th2, Th17 and Treg cells, specifically, inhibited the expressions of GATA3, IL-4, IL-6, IL-1β, RORγt, IL-17A, TNF-α and increased the secretions of IL-10, INF-γ in BALF and lung homogenate. Moreover, PNE suppressed the levels of total IgE, anti-OVA IgE, anti-OVA IgG 1 and histamine release in serum. The histological analysis showed that the fibrosis and infiltration of inflammatory cells were also ameliorated in PNE treated mice. On the other hand, PNE inhibited the allergic responses via inactivation of rat peritoneal mast cells degranulation. These results suggest that PNE has therapeutic potential for treating allergic asthma through inhibiting Th2/Th17 responses and mast cells activation. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Targets in the microenvironment of rectal cancer : A focus on angiogenic growth factors and chemokines

    NARCIS (Netherlands)

    Tamas, Karin Rita

    2015-01-01

    Cancer cells interact with each other, and with cells of the tumor microenvironment. This coincides with the production of numerous soluble factors which can stimulate cancer cell growth and migration. In addition the tumor microenvironment can facilitate cancer cells to escape the effect of

  7. Polymer drug delivery systems for effecive therapy and modulation of tumor microenvironment.

    Czech Academy of Sciences Publication Activity Database

    Šírová, Milada; Studenovský, Martin; Etrych, Tomáš; Horková, Veronika; Sivák, Ladislav; Říhová, Blanka

    2015-01-01

    Roč. 8, Supplement 1 (2015), s. 51 ISSN 1875-2292. [7th International Conference on Tumor Microenvironment. 11.10.2015-15.10.2015, Tel Aviv] R&D Projects: GA ČR(CZ) GA14-12742S Institutional support: RVO:61388971 ; RVO:61389013 Keywords : Polymer * drug * tumor microenvironment Subject RIV: EC - Immunology; CD - Macromolecular Chemistry (UMCH-V)

  8. The role of sphingosine-1-phosphate in the tumor microenvironment and its clinical implications.

    Science.gov (United States)

    Nakajima, Masato; Nagahashi, Masayuki; Rashid, Omar M; Takabe, Kazuaki; Wakai, Toshifumi

    2017-04-01

    Elucidating the interaction between cancer and non-cancer cells, such as blood vessels, immune cells, and other stromal cells, in the tumor microenvironment is imperative in understanding the mechanisms underlying cancer progression and metastasis, which is expected to lead to the development of new therapeutics. Sphingosine-1-phosphate is a bioactive lipid mediator that promotes cell survival, proliferation, migration, angiogenesis/lymphangiogenesis, and immune responsiveness, which are all factors involved in cancer progression. Sphingosine-1-phosphate is generated inside cancer cells by sphingosine kinases and then exported into the tumor microenvironment. Although sphingosine-1-phosphate is anticipated to play an important role in the tumor microenvironment and cancer progression, determining sphingosine-1-phosphate levels in the tumor microenvironment has been difficult due to a lack of established methods. We have recently developed a method to measure sphingosine-1-phosphate levels in the interstitial fluid that bathes cancer cells in the tumor microenvironment, and reported that high levels of sphingosine-1-phosphate exist in the tumor interstitial fluid. Importantly, sphingosine-1-phosphate can be secreted from cancer cells and non-cancer components such as immune cells and vascular/lymphatic endothelial cells in the tumor microenvironment. Furthermore, sphingosine-1-phosphate affects both cancer and non-cancer cells in the tumor microenvironment promoting cancer progression. Here, we review the roles of sphingosine-1-phosphate in the interaction between cancer and non-cancer cells in tumor microenvironment, and discuss future possibilities for targeted therapies against sphingosine-1-phosphate signaling for cancer patients.

  9. Perfect secure domination in graphs

    Directory of Open Access Journals (Sweden)

    S.V. Divya Rashmi

    2017-07-01

    Full Text Available Let $G=(V,E$ be a graph. A subset $S$ of $V$ is a dominating set of $G$ if every vertex in $Vsetminus  S$ is adjacent to a vertex in $S.$ A dominating set $S$ is called a secure dominating set if for each $vin Vsetminus S$ there exists $uin S$ such that $v$ is adjacent to $u$ and $S_1=(Ssetminus{u}cup {v}$ is a dominating set. If further the vertex $uin S$ is unique, then $S$ is called a perfect secure dominating set. The minimum cardinality of a perfect secure dominating set of $G$ is called the perfect  secure domination number of $G$ and is denoted by $gamma_{ps}(G.$ In this paper we initiate a study of this parameter and present several basic results.

  10. Defined three-dimensional microenvironments boost induction of pluripotency

    Science.gov (United States)

    Caiazzo, Massimiliano; Okawa, Yuya; Ranga, Adrian; Piersigilli, Alessandra; Tabata, Yoji; Lutolf, Matthias P.

    2016-03-01

    Since the discovery of induced pluripotent stem cells (iPSCs), numerous approaches have been explored to improve the original protocol, which is based on a two-dimensional (2D) cell-culture system. Surprisingly, nothing is known about the effect of a more biologically faithful 3D environment on somatic-cell reprogramming. Here, we report a systematic analysis of how reprogramming of somatic cells occurs within engineered 3D extracellular matrices. By modulating microenvironmental stiffness, degradability and biochemical composition, we have identified a previously unknown role for biophysical effectors in the promotion of iPSC generation. We find that the physical cell confinement imposed by the 3D microenvironment boosts reprogramming through an accelerated mesenchymal-to-epithelial transition and increased epigenetic remodelling. We conclude that 3D microenvironmental signals act synergistically with reprogramming transcription factors to increase somatic plasticity.

  11. Microenvironments to study migration and somal translocation in cortical neurons.

    Science.gov (United States)

    Zhao, Shifang; Fan, Wenqiang; Guo, Xiang; Xue, Longjian; Berninger, Benedikt; Salierno, Marcelo J; Del Campo, Aránzazu

    2018-02-01

    Migrating post-mitotic neurons of the developing cerebral cortex undergo terminal somal translocation (ST) when they reach their final destination in the cortical plate. This process is crucial for proper cortical layering and its perturbation can lead to brain dysfunction. Here we present a reductionist biomaterials platform that faithfully supports and controls the distinct phases of terminal ST in vitro. We developed microenvironments with different adhesive molecules to support neuronal attachment, neurite extension, and migration in distinct manners. Efficient ST occurred when the leading process of migratory neurons crossed from low-to high-adhesive areas on a substrate, promoting spreading of the leading growth cone. Our results indicate that elementary adhesive cell-substrate interactions strongly influence migratory behavior and the final positioning of neurons during their developmental journey. This in vitro model allows advanced experimentation to reveal the microenvironmental requirements underlying cortical layer development and disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. [Tumor Cells and Micro-environment in Brain Metastases].

    Science.gov (United States)

    Zhong, Wen; Hu, Chengping

    2016-09-20

    Improvements in survival and quality of life of patients with lung cancer had been achieved due to the progression of early diagnosis and precision medicine at recent years, however, until now, treatments targeted at lesions in central nervous system are far from satisfying, thus threatening livelihood of patients involved. After all, in the issue of prophylaxis and therapeutics of brain metastases, it is crucial to learn about the biological behavior of tumor cells in brain metastases and its mechanism underlying, and the hypothesis "seed and soil", that is, tumor cells would generate series of adaptive changes to fit in the new environment, is liable to help explain this process well. In this assay, we reviewed documents concerning tumor cells, brain micro-environments and their interactions in brain metastases, aiming to provide novel insight into the treatments of brain metastases.

  13. Tumor Microenvironment, a Paradigm in Hepatocellular Carcinoma Progression and Therapy

    Directory of Open Access Journals (Sweden)

    Maryam Tahmasebi Birgani

    2017-02-01

    Full Text Available Hepatocellular carcinoma (HCC is among the most lethal and prevalent cancers in the human population. Different etiological factors such as hepatitis B and C virus, alcohol and diabetes cause liver injury followed by inflammation, necrosis and hepatocytes proliferation. Continuous cycles of this destructive–regenerative process culminates in liver cirrhosis which is characterized by regenerating nodules that progress to dysplastic nodules and ultimately HCC. Despite its significance, there is only an elemental understanding of the pathogenetic mechanisms, and there are only limited therapeutic options. Therefore, the study of the involved molecular mechanisms can open a new insight to define more effective treatment strategies. A variety of alterations have been reported in HCC patients, particularly the cancer-associated microenvironment components including immune cells, fibroblast cells, endothelial cells and extracellular matrix can support the neoplastic cells to proliferate, growth and invade. This review summarizes the current state of knowledge and highlights the principal challenges that are relevant to controlling this milieu.

  14. Neuro-immune modulation of the thymus microenvironment (review).

    Science.gov (United States)

    Mignini, Fiorenzo; Sabbatini, Maurizio; Mattioli, Laura; Cosenza, Monica; Artico, Marco; Cavallotti, Carlo

    2014-06-01

    The thymus is the primary site for T-cell lympho-poiesis. Its function includes the maturation and selection of antigen specific T cells and selective release of these cells to the periphery. These highly complex processes require precise parenchymal organization and compartmentation where a plethora of signalling pathways occur, performing strict control on the maturation and selection processes of T lymphocytes. In this review, the main morphological characteristics of the thymus microenvironment, with particular emphasis on nerve fibers and neuropeptides were assessed, as both are responsible for neuro-immune‑modulation functions. Among several neurotransmitters that affect thymus function, we highlight the dopaminergic system as only recently has its importance on thymus function and lymphocyte physiology come to light.

  15. Novel "Elements" of Immune Suppression within the Tumor Microenvironment.

    Science.gov (United States)

    Gurusamy, Devikala; Clever, David; Eil, Robert; Restifo, Nicholas P

    2017-06-01

    Adaptive evolution has prompted immune cells to use a wide variety of inhibitory signals, many of which are usurped by tumor cells to evade immune surveillance. Although tumor immunologists often focus on genes and proteins as mediators of immune function, here we highlight two elements from the periodic table-oxygen and potassium-that suppress the immune system in previously unappreciated ways. While both are key to the maintenance of T-cell function and tissue homeostasis, they are exploited by tumors to suppress immuno-surveillance and promote metastatic spread. We discuss the temporal and spatial roles of these elements within the tumor microenvironment and explore possible therapeutic interventions for effective and promising anticancer therapies. Cancer Immunol Res; 5(6); 426-33. ©2017 AACR . ©2017 American Association for Cancer Research.

  16. Fabrication of highly modulable fibrous 3D extracellular microenvironments

    KAUST Repository

    Zhang, Xixiang

    2017-06-13

    Three-dimensional (3D) in vitro scaffolds that mimic the irregular fibrous structures of in vivo extracellular matrix (ECM) are critical for many important biological applications. However, structural properties modulation of fibrous 3D scaffolds remains a challenge. Here, we report the first highly modulable 3D fibrous scaffolds self-assembled by high-aspect-ratio (HAR) microfibers. The scaffolds structural properties can be easily tailored to incorporate various physical cues, including geometry, stiffness, heterogeneity and nanotopography. Moreover, the fibrous scaffolds are readily and accurately patterned on desired locations of the substrate. Cell culture exhibits that our scaffolds can elicit strong bidirectional cell-material interactions. Furthermore, a functional disparity between the two-dimensional substrate and our 3D scaffolds is identified by cell spreading and proliferation data. These results prove the potential of the proposed scaffold as a biomimetic extracellular microenvironment for cell study.

  17. Total Domination Versus Paired-Domination in Regular Graphs

    Directory of Open Access Journals (Sweden)

    Cyman Joanna

    2018-05-01

    Full Text Available A subset S of vertices of a graph G is a dominating set of G if every vertex not in S has a neighbor in S, while S is a total dominating set of G if every vertex has a neighbor in S. If S is a dominating set with the additional property that the subgraph induced by S contains a perfect matching, then S is a paired-dominating set. The domination number, denoted γ(G, is the minimum cardinality of a dominating set of G, while the minimum cardinalities of a total dominating set and paired-dominating set are the total domination number, γt(G, and the paired-domination number, γpr(G, respectively. For k ≥ 2, let G be a connected k-regular graph. It is known [Schaudt, Total domination versus paired domination, Discuss. Math. Graph Theory 32 (2012 435–447] that γpr(G/γt(G ≤ (2k/(k+1. In the special case when k = 2, we observe that γpr(G/γt(G ≤ 4/3, with equality if and only if G ≅ C5. When k = 3, we show that γpr(G/γt(G ≤ 3/2, with equality if and only if G is the Petersen graph. More generally for k ≥ 2, if G has girth at least 5 and satisfies γpr(G/γt(G = (2k/(k + 1, then we show that G is a diameter-2 Moore graph. As a consequence of this result, we prove that for k ≥ 2 and k ≠ 57, if G has girth at least 5, then γpr(G/γt(G ≤ (2k/(k +1, with equality if and only if k = 2 and G ≅ C5 or k = 3 and G is the Petersen graph.

  18. Concentration levels and source apportionment of ultrafine particles in road microenvironments

    Science.gov (United States)

    Argyropoulos, G.; Samara, C.; Voutsa, D.; Kouras, A.; Manoli, E.; Voliotis, A.; Tsakis, A.; Chasapidis, L.; Konstandopoulos, A.; Eleftheriadis, K.

    2016-03-01

    A mobile laboratory unit (MOBILAB) with on-board instrumentation (Scanning Mobility Particle Sizer, SMPS; Ambient NOx analyzer) was used to measure size-resolved particle number concentrations (PNCs) of quasi-ultrafine particles (UFPs, 9-372 nm), along with NOx, in road microenvironments. On-road measurements were carried out in and around a large Greek urban agglomeration, the Thessaloniki Metropolitan Area (TMA). Two 2-week measurement campaigns were conducted during the warm period of 2011 and the cold period of 2012. During each sampling campaign, MOBILAB was driven through a 5-day inner-city route and a second 5-day external route covering in total a wide range of districts (urban, urban background, industrial and residential), and road types (major and minor urban roads, freeways, arterial and interurban roads). All routes were conducted during working days, in morning and in afternoon hours under real-world traffic conditions. Spatial classification of MOBILAB measurements involved the assignment of measurement points to location bins defined by the aspect ratio of adjacent urban street canyons (USCs). Source apportionment was further carried out, by applying Positive Matrix Factorization (PMF) to particle size distribution data. Apportioned PMF factors were interpreted, by employing a two-step methodology, which involved (a) statistical association of PMF factor contributions with 12 h air-mass back-trajectories ending at the TMA during MOBILAB measurements, and (b) Multiple Linear Regression (MLR) using PMF factor contributions as the dependent variables, while relative humidity, solar radiation flux, and vehicle speed were used as the independent variables. The applied data analysis showed that low-speed cruise and high-load engine operation modes are the two dominant sources of UFPs in most of the road microenvironments in the TMA, with significant contributions from background photochemical processes during the warm period, explaining the reversed

  19. 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

  20. GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells.

    Directory of Open Access Journals (Sweden)

    Pierre-Yves Mantel

    2007-12-01

    Full Text Available Transcription factors act in concert to induce lineage commitment towards Th1, Th2, or T regulatory (Treg cells, and their counter-regulatory mechanisms were shown to be critical for polarization between Th1 and Th2 phenotypes. FOXP3 is an essential transcription factor for natural, thymus-derived (nTreg and inducible Treg (iTreg commitment; however, the mechanisms regulating its expression are as yet unknown. We describe a mechanism controlling iTreg polarization, which is overruled by the Th2 differentiation pathway. We demonstrated that interleukin 4 (IL-4 present at the time of T cell priming inhibits FOXP3. This inhibitory mechanism was also confirmed in Th2 cells and in T cells of transgenic mice overexpressing GATA-3 in T cells, which are shown to be deficient in transforming growth factor (TGF-beta-mediated FOXP3 induction. This inhibition is mediated by direct binding of GATA3 to the FOXP3 promoter, which represses its transactivation process. Therefore, this study provides a new understanding of tolerance development, controlled by a type 2 immune response. IL-4 treatment in mice reduces iTreg cell frequency, highlighting that therapeutic approaches that target IL-4 or GATA3 might provide new preventive strategies facilitating tolerance induction particularly in Th2-mediated diseases, such as allergy.

  1. 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.

  2. 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 Th1-type immune responses and thus contribute to the BCG success.

  3. RhIL-11 treatment normalized Th1/Th2 and T-bet/GATA-3 imbalance in in human immune thrombocytopenic purpura (ITP).

    Science.gov (United States)

    Lin, Ying; Zhou, Xieming; Guo, Wenjian; Li, Qianqian; Pan, Xiahui; Bao, Yunhua; He, Muqing; Zhu, Baoling; Lin, Xiaoji; Jin, Limin; Yao, Rongxin

    2016-09-01

    Immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disorder characterized by reduction in platelet counts. T helper 1 (Th1) cells polarization with an increased shift of Th1/Th2 ratio has been reported in ITP. This shift is associated with transcription factor T-box expressed in T cells (T-bet) upregulation and GATA-binding protein 3 (GATA-3) downregulation, leading to an increased T-bet/GATA-3 ratio. Our previous in vitro study showed that recombinant human interleukin-11 (rhIL-11) could normalize Th1/Th2 imbalance in the peripheral blood mononuclear cells (PBMCs) isolated from adult ITP patients, which co-occurred with T-bet/GATA-3 ratio restoration. In this report, we investigated whether rhIL-11 had therapeutic effect in clinical ITP patients and whether rhIL-11 treatment could normalize Th1/Th2 and T-bet/GATA-3 levels in vivo. We found rhIL-11 treatment had a response rate of 67.7% and significantly decreased Th1 and T-bet levels but increased Th2 and GATA-3 levels in ITP patients who showed good response, normalizing Th1/Th2 and T-bet/GATA-3 ratios similar to that in healthy controls. Thus our study suggested rhIL-11 was effective with tolerable adverse effects in ITP. The treatment strategy warrants further clinical investigation. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Human Breast Cancer Cells Are Redirected to Mammary Epithelial Cells upon Interaction with the Regenerating Mammary Gland Microenvironment In-Vivo

    Science.gov (United States)

    Bussard, Karen M.; Smith, Gilbert H.

    2012-01-01

    Breast cancer is the second leading cause of cancer deaths in the United States. At present, the etiology of breast cancer is unknown; however the possibility of a distinct cell of origin, i.e. a cancer stem cell, is a heavily investigated area of research. Influencing signals from the tissue niche are known to affect stem cells. Literature has shown that cancer cells lose their tumorigenic potential and display ‘normal’ behavior when placed into ‘normal’ ontogenic environments. Therefore, it may be the case that the tissue microenvironment is able to generate signals to redirect cancer cell fate. Previously, we showed that pluripotent human embryonal carcinoma cells could be redirected by the regenerating mammary gland microenvironment to contribute epithelial progeny for ‘normal’ gland development in-vivo. Here, we show that that human metastatic, non-metastatic, and metastasis-suppressed breast cancer cells proliferate and contribute to normal mammary gland development in-vivo without tumor formation. Immunochemistry for human-specific mitochondria, keratin 8 and 14, as well as human-specific milk proteins (alpha-lactalbumin, impregnated transplant hosts) confirmed the presence of human cell progeny. Features consistent with normal mammary gland development as seen in intact hosts (duct, lumen formation, development of secretory acini) were recapitulated in both primary and secondary outgrowths from chimeric implants. These results suggest the dominance of the tissue microenvironment over cancer cell fate. This work demonstrates that cultured human breast cancer cells (metastatic and non-metastatic) respond developmentally to signals generated by the mouse mammary gland microenvironment during gland regeneration in-vivo. PMID:23155468

  5. Human breast cancer cells are redirected to mammary epithelial cells upon interaction with the regenerating mammary gland microenvironment in-vivo.

    Directory of Open Access Journals (Sweden)

    Karen M Bussard

    Full Text Available Breast cancer is the second leading cause of cancer deaths in the United States. At present, the etiology of breast cancer is unknown; however the possibility of a distinct cell of origin, i.e. a cancer stem cell, is a heavily investigated area of research. Influencing signals from the tissue niche are known to affect stem cells. Literature has shown that cancer cells lose their tumorigenic potential and display 'normal' behavior when placed into 'normal' ontogenic environments. Therefore, it may be the case that the tissue microenvironment is able to generate signals to redirect cancer cell fate. Previously, we showed that pluripotent human embryonal carcinoma cells could be redirected by the regenerating mammary gland microenvironment to contribute epithelial progeny for 'normal' gland development in-vivo. Here, we show that that human metastatic, non-metastatic, and metastasis-suppressed breast cancer cells proliferate and contribute to normal mammary gland development in-vivo without tumor formation. Immunochemistry for human-specific mitochondria, keratin 8 and 14, as well as human-specific milk proteins (alpha-lactalbumin, impregnated transplant hosts confirmed the presence of human cell progeny. Features consistent with normal mammary gland development as seen in intact hosts (duct, lumen formation, development of secretory acini were recapitulated in both primary and secondary outgrowths from chimeric implants. These results suggest the dominance of the tissue microenvironment over cancer cell fate. This work demonstrates that cultured human breast cancer cells (metastatic and non-metastatic respond developmentally to signals generated by the mouse mammary gland microenvironment during gland regeneration in-vivo.

  6. Total glucosides of peony ameliorates Sjögren's syndrome by affecting Th1/Th2 cytokine balance.

    Science.gov (United States)

    Wu, Guolin; Wu, Nayuan; Li, Tianyi; Lu, Wenwen; Yu, Guoyou

    2016-03-01

    The present study aimed to investigate the molecular mechanisms underlying the effects of total glucosides of peony (TGP) in the treatment of Sjögren's syndrome (SS). A total of 40 mice with SS were evenly assigned into four groups, including: Control group; TGP group, receiving 1 mg TGP daily; hydroxychloroquine (HCQ) group, receiving 0.25 mg HCQ daily; and a combined group, receiving 1 mg TGP and 0.25 mg HCQ daily. After 8 weeks, quantitative polymerase chain reaction and an enzyme-linked immunosorbent assay were used to detect the levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), Fas and FasL in each group of mice. In addition, immunohistochemical analysis was used to determine the expression levels of IFN-γ and IL-4. IFN-γ, IL-4, Fas and FasL levels were significantly increased in the control group compared with the other three groups (PTGP and combined groups compared with the control group (PTGP ameliorates SS by affecting the Th1/Th2 cytokine balance and decreasing the expression levels of IFN-γ, IL-4, Fas and FasL. Therefore, TGP may represent a potential novel therapeutic agent for the treatment of SS.

  7. Multiple Exposures to Ascaris suum Induce Tissue Injury and Mixed Th2/Th17 Immune Response in Mice.

    Science.gov (United States)

    Nogueira, Denise Silva; Gazzinelli-Guimarães, Pedro Henrique; Barbosa, Fernando Sérgio; Resende, Nathália Maria; Silva, Caroline Cavalcanti; de Oliveira, Luciana Maria; Amorim, Chiara Cássia Oliveira; Oliveira, Fabrício Marcus Silva; Mattos, Matheus Silvério; Kraemer, Lucas Rocha; Caliari, Marcelo Vidigal; Gaze, Soraya; Bueno, Lilian Lacerda; Russo, Remo Castro; Fujiwara, Ricardo Toshio

    2016-01-01

    Ascaris spp. infection affects 800 million people worldwide, and half of the world population is currently at risk of infection. Recurrent reinfection in humans is mostly due to the simplicity of the parasite life cycle, but the impact of multiple exposures to the biology of the infection and the consequences to the host's homeostasis are poorly understood. In this context, single and multiple exposures in mice were performed in order to characterize the parasitological, histopathological, tissue functional and immunological aspects of experimental larval ascariasis. The most important findings revealed that reinfected mice presented a significant reduction of parasite burden in the lung and an increase in the cellularity in the bronchoalveolar lavage (BAL) associated with a robust granulocytic pulmonary inflammation, leading to a severe impairment of respiratory function. Moreover, the multiple exposures to Ascaris elicited an increased number of circulating inflammatory cells as well as production of higher levels of systemic cytokines, mainly IL-4, IL-5, IL-6, IL-10, IL-17A and TNF-α when compared to single-infected animals. Taken together, our results suggest the intense pulmonary inflammation associated with a polarized systemic Th2/Th17 immune response are crucial to control larval migration after multiple exposures to Ascaris.

  8. The Contribution of Allergen-Specific IgG to the Development of Th2-Mediated Airway Inflammation

    Directory of Open Access Journals (Sweden)

    Jesse W. Williams

    2012-01-01

    Full Text Available In both human asthmatics and animal models of allergy, allergen-specific IgG can contribute to Th2-mediated allergic inflammation. Mouse models have elucidated an important role for IgG and Fc-gamma receptor (FcγR signaling on antigen presenting cells (APC for the induction of airway inflammation. These studies suggest a positive feedback loop between IgG produced by the adaptive B cell response and FcγR signaling on innate immune cells. Studies of IgG and FcγRs in humans with asthma or allergic lung disease have been more controversial. Some reports have identified associations between allergen-specific IgG and severity of allergic responses, while other studies have found associations of IgG subclass IgG4 with allergic tolerance. In this paper, we review the literature to help define the nature of IgG and FcγR signaling on innate immune cells and how it contributes to the development of allergic immune responses.

  9. A phase trial of the oral Lactobacillus casei vaccine polarizes Th2 cell immunity against transmissible gastroenteritis coronavirus infection.

    Science.gov (United States)

    Jiang, Xinpeng; Hou, Xingyu; Tang, Lijie; Jiang, Yanping; Ma, Guangpeng; Li, Yijing

    2016-09-01

    Transmissible gastroenteritis coronavirus (TGEV) is a member of the genus Coronavirus, family Coronaviridae, order Nidovirales. TGEV is an enteropathogenic coronavirus that causes highly fatal acute diarrhoea in newborn pigs. An oral Lactobacillus casei (L. casei) vaccine against anti-transmissible gastroenteritis virus developed in our laboratory was used to study mucosal immune responses. In this L. casei vaccine, repetitive peptides expressed by L. casei (specifically the MDP and tuftsin fusion protein (MT)) were repeated 20 times and the D antigenic site of the TGEV spike (S) protein was repeated 6 times. Immunization with recombinant Lactobacillus is crucial for investigations of the effect of immunization, such as the first immunization time and dose. The first immunization is more important than the last immunization in the series. The recombinant Lactobacillus elicited specific systemic and mucosal immune responses. Recombinant L. casei had a strong potentiating effect on the cellular immunity induced by the oral L. casei vaccine. However, during TGEV infection, the systemic and local immune responses switched from Th1 to Th2-based immune responses. The systemic humoral immune response was stronger than the cellular immune response after TGEV infection. We found that the recombinant Lactobacillus stimulated IL-17 expression in both the systemic and mucosal immune responses against TGEV infection. Furthermore, the Lactobacillus vaccine stimulated an anti-TGEV infection Th17 pathway. The histopathological examination showed tremendous potential for recombinant Lactobacillus to enable rapid and effective treatment for TGEV with an intestinal tropism in piglets. The TGEV immune protection was primarily dependent on mucosal immunity.

  10. Correlation of Local FOXP3-Expressing T Cells and Th1-Th2 Balance in Perennial Allergic Nasal Mucosa

    Directory of Open Access Journals (Sweden)

    Hideaki Shirasaki

    2011-01-01

    Full Text Available Regulatory T cells (Treg play some important roles in allergic rhinitis. The most specific marker for Treg is FOXP3, a recently identified transcription factor that is essential for Treg development. In order to clarify the levels of Treg in allergic nasal mucosa, we studied the relationship between FOXP3-expressing cells and Th1-Th2 balance in nasal mucosa by means of immunohistochemistry. Human turbinates were obtained after turbinectomy from 26 patients (14 patients with perennial allergic rhinitis and 12 patients with nonallergic rhinitis. To identify the cells expressing the FOXP3 protein, double immunostaining was performed by using anti-FOXP3 antibody and anti-CD3 antibody. There was no significant difference in the percentage of FOXP3+CD3+ cells among CD3+ cells in the nasal mucosa of two groups. The proportion of FOXP3+CD3+ cells tend to be correlated positively with GATA3+CD3+ cells/T-bet+CD3+ cells ratio (=0.56, =0.04. A positive correlation with GATA3+CD3+/T-bet+CD3+ ratio and FOXP3+CD3+/CD3+ ratio suggests the role of local regulatory T cells as a minimal control of the chronic allergen exposure in nasal mucosa.

  11. Role of Cyclooxygenase-2 Pathway in Creating an Immunosuppressive Microenvironment and in Initiation and Progression of Wilms' Tumor

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    Paramahamsa Maturu

    2017-03-01

    Full Text Available Wilms' tumors (WT, which accountfor 6% of all childhood cancers, arise from dysregulated differentiation of nephrogenic progenitor cells from embryonic kidneys. Though there is an improvement in the prognosis of WT, still 10% of patients with WT die due to recurrence. Thus more effective treatment approaches are necessary. We previously characterized the inflammatory microenvironment in human WT and observed the robust expression of COX-2. The aim of this study was to extend our studies to analyze the role of COX-2 pathway components in WT progression using a mouse model of WT. Herein, COX-2 pathway components such as COX-2, HIF1-α, p-ERK1/2, and p-STAT3 were upregulated in mouse and human tumor tissues. In our RPPA analysis, COX-2 was up-regulated in M15 cells after Wt1 gene was knocked down. Flow cytometry analysis showed the increased infiltration of immune suppressive inflammatory cells such as pDC's and Treg cells in tumors. The chemotactic chemokines responsible for the infiltration of these cells were also induced in CCR5 and CXCR4 dependent manner respectively. The immunosuppressive cytokines IL-10, TGF-β, and TNF-α were also up-regulated. Furthermore, more pronounced Th2 and Treg induced cytokine response was observed than Th1 response in tumors. Basing on all these evidences it is speculated that COX-2 pathway may be a beneficial target for the treatment of WT. It may be most effective as an adjuvant therapy together with other inhibitors. Thus, our current study provides a good rationale for initiating animal studies to confirm the efficacy of COX-2 inhibitors in decreasing tumor cell growth in vivo.

  12. Different populations of CD11b+ dendritic cells drive Th2 responses in the small intestine and colon

    DEFF Research Database (Denmark)

    Mayer, Johannes U.; Demiri, Mimoza; Agace, William Winston

    2017-01-01

    and Schistosoma mansoni eggs do not develop in mice with IRF-4-deficient DCs (IRF-4f/f CD11c-cre). Adoptive transfer of conventional DCs, in particular CD11b-expressing DCs from the intestine, is sufficient to prime S. mansoni-specific Th2 responses. Surprisingly, transferred IRF-4-deficient DCs also effectively...... prime S. mansoni-specific Th2 responses. Egg antigens do not induce the expression of IRF-4-related genes. Instead, IRF-4f/f CD11c-cre mice have fewer CD11b+ migrating DCs and fewer DCs carrying parasite antigens to the lymph nodes. Furthermore, CD11b+ CD103+ DCs induce Th2 responses in the small...

  13. The evolution of the Th2 immune responses and its relationships with parasitic diseases and allergy Consideraciones sobre la evolución de la respuesta inmunitaria Th2 y sus posibles relaciones con parasitosis y alergia

    Directory of Open Access Journals (Sweden)

    Luis Caraballo

    2011-09-01

    Full Text Available

    A variety of links occur between parasites, particularly helminths, and allergic diseases--both common conditions of epidemiological importance in tropical regions. Although speculations are often made about the effects of parasitic diseases on the evolution of the immune system, the selective forces that have shaped the allergic response are unknown and probably include evolutionary mechanisms different to those traditionally reported. Helminths, infectious and antigenic sources that induce allergiclike responses, established themselves as parasites in organisms that already had cell groups related to the type 2 immunity. An essential component in the relationship between helminths and their hosts is that the former induce immunosuppression, creating a kind of balance that allows the survival of both. The development of this equilibrium undoubtedly includes adaptations in both organisms, and the survival of the parasite is the result of (a acquiring immune suppressor mechanisms and (b finding hosts with lower intensity of the type 2 response. This in turn suggests that although helminth infections have influenced the formation of type 2 immunity, they have not been an important selective force in the
    particular case of allergic response. The latter is more related to an exaggerated Th2/IgE response.

    Hay diversos vínculos entre las parasitosis, especialmente las helmintiasis, y las enfermedades alérgicas, ambas condiciones de importancia epidemiológica en las regiones tropicales. Mientras que se ha especulado con frecuencia los efectos de las enfermedades parasitarias sobre la evolución del sistema inmunitario, no se conocen las fuerzas selectivas que han moldeado la respuesta alérgica y pensamos que incluyen mecanismos evolutivos distintos a los tradicionalmente divulgados.
    Los helmintos, fuente infecciosa y antigénica inductora de una respuesta parecida a la alérgica, se establecieron como parásitos en huéspedes que

  14. Dominance Hierarchies in Young Children

    Science.gov (United States)

    Edelman, Murray S.; Omark, Donald R.

    1973-01-01

    This study uses the ethological approach of seeking species characteristics and phylogenetic continuities in an investigation of human behavior. Among primates a striking consistency is the presence of some form of dominance hierarchy in many species. The present study examines peer group dominance hierarchies as they are perceived by children in…

  15. Dominant Leadership Style in Schools

    Science.gov (United States)

    Rajbhandari, Mani Man Singh

    2006-01-01

    The dominant leadership style is defined by the situation and the kind of organizational environment and climate. This, however, does not sufficiently define the leadership qualities in school organizations. There are other factors which also determine the dominant leadership style, which are the traits and style, teachers commitments, pass out…

  16. Activation of mixed glia by Abeta-specific Th1 and Th17 cells and its regulation by Th2 cells.

    Science.gov (United States)

    McQuillan, K; Lynch, Marina A; Mills, Kingston H G

    2010-05-01

    Microglia are innate immune cells of the CNS, that act as antigen-presenting cells (APC) for antigen-specific T cells and respond to inflammatory stimuli, such as amyloid-beta (Abeta), resulting in the release of neurotoxic factors and pro-inflammatory cytokines. Astrocytes can also act as APC and modulate the function of microglia. However, the role of distinct T cell subtypes, in particular Th17 cells, in glial activation and subsequent modulatory effects of Th2 cells are poorly understood. Here, we generated Abeta-specific Th1, Th2, and Th17 cells and examined their role in modulating Abeta-induced activation of microglia in a mixed glial culture, a preparation which mimics the complex APC types in the brain. We demonstrated that mixed glia acted as an effective APC for Abeta-specific Th1 and Th17 cells. Addition of Abeta-specific Th2 cells suppressed the Abeta-induced IFN-gamma production by Th1 cells and IL-17 production by Th17 cells with glia as the APC. Co-culture of Abeta-specific Th1 or Th17 cells with glia markedly enhanced Abeta-induced pro-inflammatory cytokine production and expression of MHC class II and co-stimulatory molecules on the microglia. Addition of Abeta-specific Th2 cells inhibited Th17 cell-induced IL-1beta and IL-6 production by mixed glia and attenuated Th1 cell-induced CD86 and CD40 expression on microglia. The modest enhancement of MHC class II and CD86 expression on astrocytes by Abeta-specific Th1 and Th17 was not attenuated by Th2 cells. These data indicate that Abeta-specific Th1 and Th17 cells induce inflammatory activation of glia, and that this is in part regulated by Th2 cells. Copyright 2010 Elsevier Inc. All rights reserved.

  17. 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.

  18. Downregulation of T-bet/GATA-3 ratio induced by IL-11 treatment is responsible for Th1/Th2 balance restoration in human immune thrombocytopenic purpura (ITP).

    Science.gov (United States)

    Yao, Rongxin; Lin, Ying; Li, Qianqian; Zhou, Xieming; Pan, Xiahui; Bao, Yunhua; He, Muqing; Zhu, Baoling; Guo, Wenjian; Lin, Xiaoji; Jin, Limin

    2014-01-01

    Abnormal cellular immunity induced by deranged Th1/Th2 profile has been revealed to play a critical role in the pathogenesis of immune thrombocytopenic purpura (ITP). Correction of the shifted Th1/Th2 balance represents a potential therapeutic approach to treat ITP. Here, we investigated the effects of IL-11 on the restoration of Th1/Th2 balance in the peripheral blood mononuclear cells (PBMCs) isolated from adult ITP patients. As shown here, we observed a higher ratio of T-bet/GATA-3 gene expression by quantitative real-time PCR in the PBMCs from ITP patients, consistent with the presence of an abnormally high Th1/Th2 ratio. Remarkably, upon IL-11 treatment, a reversal of T-bet/GATA-3 ratio in ITP was achieved and was shown to be responsible for the restoration of Th1/Th2 balance, with IL-11 at 100 ng/ml demonstrating the highest efficiency. T-bet and GATA-3 are the two transcriptional factors that have been indicated to be the master regulators for Th1 and Th2 lineage commitment, respectively. In the presence of 100 ng/ml IL-11, GATA-3 transcript abundance rose up to ~85-fold of that measured in untreated cells, whereas T-bet transcripts were lowered merely to ~41%, suggesting that GATA-3 was the major contributor for the reversal of T-bet/GATA-3 ratio. Thus, our findings may very well encourage the development of novel medicines that specifically target and correct the T-bet/GATA-3 imbalance identified in ITP.

  19. Bone marrow micro-environment is a crucial player for myelomagenesis and disease progression.

    Science.gov (United States)

    Mondello, Patrizia; Cuzzocrea, Salvatore; Navarra, Michele; Mian, Michael

    2017-03-21

    Despite the advent of many therapeutic agents, such as bortezomib and lenalidomide that have significantly improved the overall survival, multiple myeloma remains an incurable disease. Failure to cure is multifactorial and can be attributed to the underlying genetic heterogeneity of the cancer and to the surrounding micro-environment. Understanding the mutual interaction between myeloma cells and micro-environment may lead to the development of novel treatment strategies able to eradicate this disease. In this review we discuss the principal molecules involved in the micro-environment network in multiple myeloma and the currently available therapies targeting them.

  20. Subjective Evaluation of the Microenvironment Generated by a Hospital Bed with Localized Ventilation System

    DEFF Research Database (Denmark)

    Kehayova, Nushka; Bolashikov, Zhecho Dimitrov; Melikov, Arsen Krikor

    2016-01-01

    A novel method for local hospital bed ventilation, called HBIVCU (Hospital Bed with Integrated Ventilation and Cleansing Unit), was studied in a human subject experiment. The goal of this study was to identify human response to the microenvironment generated by a hospital bed with installed HBIVCU...... and to compare with human response to the micro-environment at a hospital bed without local ventilation. 32 participants took part in two experimental conditions - hospital bed with and without installed HBIVCU. Subject’s votes on the bed microenvironment were collected via standardized questionnaires...

  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. Langerhans cell-like dendritic cells stimulated with an adjuvant direct the development of Th1 and Th2 cells in vivo.

    Science.gov (United States)

    Matsui, K; Mori, A; Ikeda, R

    2015-10-01

    It is well known that Langerhans cells (LCs) work as the primary orchestrators in the polarization of immune responses towards a T helper type 1 (Th1) or Th2 milieu. In this study, we attempted to generate LCs from murine bone marrow cells and elicit a Th1- or Th2-prone immune response through the LCs after stimulation with Th1 or Th2 adjuvant. LCs were generated from murine bone marrow cells using granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4 and transforming growth factor (TGF)-β, and were obtained as I-A(d) positive cells. Mice were primed with Th1/Th2 adjuvant- and ovalbumin (OVA)-pulsed LCs and then given a booster injection of OVA 2 days later via the hind footpad. Five days after the OVA injection, the cytokine response in the draining popliteal lymph nodes was investigated by reverse transcription-polymerase chain reaction (RT-PCR) flow cytometry and enzyme-linked immunosorbent assay (ELISA). The generated LCs expressed typical LC surface markers, E-cadherin and Langerin, and were classified accordingly as LC-like dendritic cells (LDCs). Administration of Th1 adjuvant, cytosine-phosphate-guanosine (CpG)-DNA- and OVA-pulsed LDCs into the hind footpads of mice induced a Th1-prone immune response, as represented by up-regulation of IFN-γ production and down-regulation of IL-4 production in the lymph node cells. Conversely, Th2 adjuvant, histamine-pulsed LDCs induced a Th2-prone immune response, as represented by up-regulation of IL-4 production and down-regulation of IFN-γ production. These results suggest that LDCs may be used as a substitute for LCs and have the ability to induce the development of Th1 and Th2 cells in vivo. Our experimental system would therefore be useful for screening of inhibitors of Th1/Th2 differentiation in order to control allergic disease. © 2015 British Society for Immunology.

  3. The influence of hydro-ethanolic extract of Portulaca oleracea L. on Th1/Th2 balance in isolated human lymphocytes.

    Science.gov (United States)

    Askari, Vahid Reza; Rezaee, Seyed Abdolrahim; Abnous, Khalil; Iranshahi, Mehrdad; Boskabady, Mohammad Hossein

    2016-12-24

    The anti-inflammatory and anti-oxidants activity of Portulaca oleracea L. (P. oleracea) were mentioned in traditional texts. In previous studies, different anti-inflammatory and anti-oxidant effects of P. oleracea were demonstrated. However, the mechanism of action and immunomodulatory property of this plant are greatly unknown. In the present study, the effect of the extract of this plant on IL-4, IL10, IFN-γ and T helper (h)1/Th2 balance in non-stimulated and stimulated human lymphocytes was examined. The effect of three concentrations (160, 40 and 10µg/ml) of P. oleracea or dexamethasone were evaluated on percentage of cell proliferation and nitric oxide (NO) production as well as secretion of cytokines (IL-4, IL10 and IFN-γ) in PHA-stimulated and non-stimulated lymphocytes, and compared to control and dexamethasone as positive control (n=15 for each group). In stimulated cells, dexamethasone significantly inhibited the percentage of cell proliferation, NO production, and secretion of cytokines in comparison to control group (P<0.001 for all cases). The percentage of cell proliferation, NO production, and secretion of cytokines were significantly decreased while Th1/Th2 (IFN-γ/IL-4) and Treg/Th2 (IL-10/IL-4) balances significantly enhanced in treated groups with all three concentrations of extract compared to control group (P<0.001 for all cases). The effect of all concentrations of the extract on cell proliferation, NO production and secretion of cytokines as well as Treg/Th2 balance were significantly lower than dexamethasone (P<0.001 for all cases), but Th1/Th2 ratio obtained in the presence of only low extract concentration was lower than dexamethasone (P<0.01). Different concentrations of extract promoted Th1/Th2 and Treg/Th2 balances which may suggest the therapeutic value of the plant in inflammatory disease associated with decreased Th1/Th2 balance such as asthma or cancers. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Exosomal tetraspanins mediate cancer metastasis by altering host microenvironment.

    Science.gov (United States)

    Lu, Jun; Li, Jun; Liu, Shuo; Wang, Teng; Ianni, Alessandro; Bober, Eva; Braun, Thomas; Xiang, Rong; Yue, Shijing

    2017-09-22

    The metastases of malignant tumors develop through a cascade of events. The establishment of a pre-metastatic micro-environment is initiated by communication between tumors and host. Exosomes come into focus as the most potent intercellular communicators playing a pivotal role in this process. Cancer cells release exosomes into the extracellular environment prior to metastasis. Tetraspanin is a type of 4 times transmembrane proteins. It may be involved in cell motility, adhesion, morphogenesis, as well as cell and vesicular membrane fusion. The exosomal tetraspanin network is a molecular scaffold connecting various proteins for signaling transduction. The complex of tetraspanin-integrin determines the recruiting cancer exosomes to pre-metastatic sites. Tetraspanin is a key element for the target cell selection of exosomes uptake that may lead to the reprogramming of target cells. Reprogrammed target cells assist pre-metastatic niche formation. Previous reviews have described the biogenesis, secretion and intercellular interaction of exosomes in various tumors. However, there is a lack of reviews on the topic of exosomal tetraspanin in the context of cancer. In this review, we will describe the main characteristics of exosomal tetraspanin in cancer cells. We will also discuss how the cancer exosomal tetraspanin alters extracellular environment and regulates cancer metastasis.

  5. Natural Compounds Regulate Glycolysis in Hypoxic Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Jian-Li Gao

    2015-01-01

    Full Text Available In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect. Recently it became a therapeutically interesting strategy and is considered as an emerging hallmark of cancer. Hypoxia inducible factor-1 (HIF-1 is one of the key transcription factors that play major roles in tumor glycolysis and could directly trigger Warburg effect. Thus, how to inhibit HIF-1-depended Warburg effect to assist the cancer therapy is becoming a hot issue in cancer research. In fact, HIF-1 upregulates the glucose transporters (GLUT and induces the expression of glycolytic enzymes, such as hexokinase, pyruvate kinase, and lactate dehydrogenase. So small molecules of natural origin used as GLUT, hexokinase, or pyruvate kinase isoform M2 inhibitors could represent a major challenge in the field of cancer treatment. These compounds aim to suppress tumor hypoxia induced glycolysis process to suppress the cell energy metabolism or enhance the susceptibility of tumor cells to radio- and chemotherapy. In this review, we highlight the role of natural compounds in regulating tumor glycolysis, with a main focus on the glycolysis under hypoxic tumor microenvironment.

  6. Prostatic microenvironment in senescence: fibroblastic growth factors × hormonal imbalance.

    Science.gov (United States)

    Hetzl, A C; Montico, F; Lorencini, R M; Kido, L A; Cândido, E M; Cagnon, V H A

    2014-05-01

    The aim was to characterize and correlate steroid hormone receptors with the FGF2, FGF7 and FGF8 reactivities in the prostatic epithelium and stroma in senile rats. Fifty male senile rats and 10 young male rats were divided into the young (YNG), the senile groups (SE), the castrated group (CAS), the estrogen-deficient group (ED), the castrated + estrogen group (CASE), and the estrogen-deficient + androgen group (EDTEST). The ventral prostate was submitted to immunohistochemical and Western blotting analyses. The results showed decreased AR and ERβ levels and increased ERα in the senile animals in relation to YNG group. Increased ERα and ERβ reactivities presenting differential localization were characterized in the CASE group compared to the CAS group. Increased FGF2 level was observed in the stroma of the CAS and ED groups in relation to the SE group and in the epithelium of the ED group in relation to the other groups. Increased and differential immunolocalization of FGF7 levels were observed in the CAS, ED and CASE groups. The FGF8 levels showed differential localization in the CAS and ED groups compared to the senile group. The intense hormone ablation was favorable to the autocrine signaling of FGF2 and FGF8. FGF7 could be activated in the androgen-independent via considering the increased FGF7 in the castrated rats. We concluded that hormone ablation in senescence was favorable to activation or/and to fibroblast signaling in the prostatic microenvironment.

  7. Acidity generated by the tumor microenvironment drives local invasion.

    Science.gov (United States)

    Estrella, Veronica; Chen, Tingan; Lloyd, Mark; Wojtkowiak, Jonathan; Cornnell, Heather H; Ibrahim-Hashim, Arig; Bailey, Kate; Balagurunathan, Yoganand; Rothberg, Jennifer M; Sloane, Bonnie F; Johnson, Joseph; Gatenby, Robert A; Gillies, Robert J

    2013-03-01

    The pH of solid tumors is acidic due to increased fermentative metabolism and poor perfusion. It has been hypothesized that acid pH promotes local invasive growth and metastasis. The hypothesis that acid mediates invasion proposes that H(+) diffuses from the proximal tumor microenvironment into adjacent normal tissues where it causes tissue remodeling that permits local invasion. In the current work, tumor invasion and peritumoral pH were monitored over time using intravital microscopy. In every case, the peritumoral pH was acidic and heterogeneous and the regions of highest tumor invasion corresponded to areas of lowest pH. Tumor invasion did not occur into regions with normal or near-normal extracellular pH. Immunohistochemical analyses revealed that cells in the invasive edges expressed the glucose transporter-1 and the sodium-hydrogen exchanger-1, both of which were associated with peritumoral acidosis. In support of the functional importance of our findings, oral administration of sodium bicarbonate was sufficient to increase peritumoral pH and inhibit tumor growth and local invasion in a preclinical model, supporting the acid-mediated invasion hypothesis. Cancer Res; 73(5); 1524-35. ©2012 AACR. ©2012 AACR.

  8. GPS-based Microenvironment Tracker (MicroTrac) Model to ...

    Science.gov (United States)

    A critical aspect of air pollution exposure assessment is the estimation of the time spent by individuals in various microenvironments (ME). Accounting for the time spent in different ME with different pollutant concentrations can reduce exposure misclassifications, while failure to do so can add uncertainty and bias to risk estimates. In this study, a classification model, called MicroTrac, was developed to estimate time of day and duration spent in eight ME (indoors and outdoors at home, work, school; inside vehicles; other locations) from global positioning system (GPS) data and geocoded building boundaries. Based on a panel study, MicroTrac estimates were compared to 24 h diary data from 7 participants on workdays and 2 participants on nonworkdays, with corresponding GPS data and building boundaries of home, school, and work. MicroTrac correctly classified the ME for 99.5% of the daily time spent by the participants. The capability of MicroTrac could help to reduce the time-location uncertainty in air pollution exposure models and exposure metrics for individuals in health studies. The National Exposure Research Laboratory’s (NERL’s) Human Exposure and Atmospheric Sciences Division (HEASD) conducts research in support of EPA’s mission to protect human health and the environment. HEASD’s research program supports Goal 1 (Clean Air) and Goal 4 (Healthy People) of EPA’s strategic plan. More specifically, our division conducts research to characterize

  9. Lymphotoxin-sensitive microenvironments in homeostasis and inflammation

    Directory of Open Access Journals (Sweden)

    Bryant eBoulianne

    2012-07-01

    Full Text Available Stromal cell micro-microenvironments within lymphoid tissues are designed to support immune cell homeostasis and to regulate ongoing immune responses to pathogens. Such stromal cell networks have been best characterized within lymphoid tissues including the spleen and peripheral lymph nodes, and systems for classifying stromal cell phenotypes and functions are emerging. In response to inflammation, stromal cell networks within lymphoid tissues change in order to accommodate and regulate lymphocyte activation. Local inflammation in non-lymphoid tissues can also induce de novo formation of lymphoid aggregates, which we term here "follicle-like structures". Of note, the stromal cell networks that underpin such follicles are not as well characterized and may be different depending on the anatomical site. However, one common element that is integral to the maintenance of stromal cell environments, either in lymphoid tissue or extra-lymphoid sites, is the constitutive regulation of stromal cell phenotype and/or function by the Lymphotoxin (LT pathway. Here we discuss how the LT pathway influences stromal cell environments both in homeostasis and in the context of inflammation in lymphoid and non-lymphoid tissues.

  10. Model of spacecraft atomic oxygen and solar exposure microenvironments

    Science.gov (United States)

    Bourassa, R. J.; Pippin, H. G.

    1993-01-01

    Computer models of environmental conditions in Earth orbit are needed for the following reasons: (1) derivation of material performance parameters from orbital test data, (2) evaluation of spacecraft hardware designs, (3) prediction of material service life, and (4) scheduling spacecraft maintenance. To meet these needs, Boeing has developed programs for modeling atomic oxygen (AO) and solar radiation exposures. The model allows determination of AO and solar ultraviolet (UV) radiation exposures for spacecraft surfaces (1) in arbitrary orientations with respect to the direction of spacecraft motion, (2) overall ranges of solar conditions, and (3) for any mission duration. The models have been successfully applied to prediction of experiment environments on the Long Duration Exposure Facility (LDEF) and for analysis of selected hardware designs for deployment on other spacecraft. The work on these models has been reported at previous LDEF conferences. Since publication of these reports, a revision has been made to the AO calculation for LDEF, and further work has been done on the microenvironments model for solar exposure.

  11. The Interaction Between Human Papillomaviruses and the Stromal Microenvironment.

    Science.gov (United States)

    Woodby, B; Scott, M; Bodily, J

    2016-01-01

    Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that replicate in stratified squamous epithelia and cause a variety of malignancies. Current efforts in HPV biology are focused on understanding the virus-host interactions that enable HPV to persist for years or decades in the tissue. The importance of interactions between tumor cells and the stromal microenvironment has become increasingly apparent in recent years, but how stromal interactions impact the normal, benign life cycle of HPVs, or progression of lesions to cancer is less understood. Furthermore, how productively replicating HPV impacts cells in the stromal environment is also unclear. Here we bring together some of the relevant literature on keratinocyte-stromal interactions and their impacts on HPV biology, focusing on stromal fibroblasts, immune cells, and endothelial cells. We discuss how HPV oncogenes in infected cells manipulate other cells in their environment, and, conversely, how neighboring cells may impact the efficiency or course of HPV infection. © 2016 Elsevier Inc. All rights reserved.

  12. CAF cellular glycolysis: linking cancer cells with the microenvironment.

    Science.gov (United States)

    Roy, Amrita; Bera, Soumen

    2016-07-01

    Cancers have long being hallmarked as cells relying heavily on their glycolysis for energy generation in spite of having functional mitochondria. The metabolic status of the cancer cells have been revisited time and again to get better insight into the overall carcinogenesis process which revealed the apparent crosstalks between the cancer cells with the fibroblasts present in the tumour microenvironment. This review focuses on the mechanisms of transformations of normal fibroblasts to cancer-associated fibroblasts (CAF), the participation of the CAF in tumour progression with special interest to the role of CAF cellular glycolysis in the overall tumorigenesis. The fibroblasts, when undergoes the transformation process, distinctly switches to a more glycolytic phenotype in order to provide the metabolic intermediates necessary for carrying out the mitochondrial pathways of ATP generation in cancer cells. This review will also discuss the molecular mechanisms responsible for this metabolic make over promoting glycolysis in CAF cells. A thorough investigation of the pathways and molecules involved will not only help in understanding the process of activation and metabolic reprogramming in CAF cells but also might open up new targets for cancer therapy.

  13. Natural compounds regulate glycolysis in hypoxic tumor microenvironment.

    Science.gov (United States)

    Gao, Jian-Li; Chen, Ying-Ge

    2015-01-01

    In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect). Recently it became a therapeutically interesting strategy and is considered as an emerging hallmark of cancer. Hypoxia inducible factor-1 (HIF-1) is one of the key transcription factors that play major roles in tumor glycolysis and could directly trigger Warburg effect. Thus, how to inhibit HIF-1-depended Warburg effect to assist the cancer therapy is becoming a hot issue in cancer research. In fact, HIF-1 upregulates the glucose transporters (GLUT) and induces the expression of glycolytic enzymes, such as hexokinase, pyruvate kinase, and lactate dehydrogenase. So small molecules of natural origin used as GLUT, hexokinase, or pyruvate kinase isoform M2 inhibitors could represent a major challenge in the field of cancer treatment. These compounds aim to suppress tumor hypoxia induced glycolysis process to suppress the cell energy metabolism or enhance the susceptibility of tumor cells to radio- and chemotherapy. In this review, we highlight the role of natural compounds in regulating tumor glycolysis, with a main focus on the glycolysis under hypoxic tumor microenvironment.

  14. Peritoneal inflammation – A microenvironment for Epithelial Ovarian Cancer (EOC

    Directory of Open Access Journals (Sweden)

    Liu Jinsong

    2004-06-01

    Full Text Available Abstract Epithelial ovarian cancer (EOC is a significant cause of cancer related morbidity and mortality in women. Preferential involvement of peritoneal structures contributes to the overall poor outcome in EOC patients. Advances in biotechnology, such as cDNA microarray, are a product of the Human Genome Project and are beginning to provide fresh opportunities to understand the biology of EOC. In particular, it is now possible to examine in depth, at the molecular level, the complex relationship between the tumor itself and its surrounding microenvironment. This review focuses on the anatomy, physiology, and current immunobiologic research of peritoneal structures, and addresses certain potentially useful animal models. Changes in both the inflammatory and non-inflammatory cell compartments, as well as alterations to the extracellular matrix, appear to be signal events that contribute to the remodeling effects of the peritoneal stroma and surface epithelial cells on tumor growth and spread. These alterations may involve a number of proteins, including cytokines, chemokines, growth factors, either membrane or non-membrane bound, and integrins. Interactions between these molecules and molecular structures within the extracellular matrix, such as collagens and the proteoglycans, may contribute to a peritoneal mesothelial surface and stromal environment that is conducive to tumor cell proliferation and invasion. These alterations need to be examined and defined as possible prosnosticators and as therapeutic or diagnostic targets.

  15. Influence of the neural microenvironment on prostate cancer.

    Science.gov (United States)

    Coarfa, Christian; Florentin, Diego; Putluri, NagiReddy; Ding, Yi; Au, Jason; He, Dandan; Ragheb, Ahmed; Frolov, Anna; Michailidis, George; Lee, MinJae; Kadmon, Dov; Miles, Brian; Smith, Christopher; Ittmann, Michael; Rowley, David; Sreekumar, Arun; Creighton, Chad J; Ayala, Gustavo

    2018-02-01

    Nerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease. We denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy. Bilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non-neoplastic epithelial cells. Nerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer. © 2017 The Authors. The Prostate Published by Wiley Periodicals, Inc.

  16. The clinical severity score of chronic actinic dermatitis correlates with in vivo photoallergic reactions and the immunologic parameters related to a shift towards Th2 immunity from the Th2/Th1 balanced status in patients with chronic actinic dermatitis.

    Science.gov (United States)

    Ko, Dong-Yeob; Choi, Seung-Hwan; Ha, Seung-Min; Kim, Tae-Hoon; Song, Ki-Hoon; Kim, Kyeong Hee; Kim, Ki-Ho

    2016-07-01

    Chronic actinic dermatitis (CAD) has a more complicated pathogenetic basis than others. The clinical grading system and its correlations with the clinical and immunological parameters still remained to be investigated to define the nature of CAD in a more detailed manner. We investigated correlations of the clinical severity score of CAD (CSS-CAD) with the clinical and immunological parameters. We evaluated 72 patients with CAD and classified them into three groups according to the CSS-CAD. We analysed total IgE level, peripheral blood (PB) eosinophil count, the ratio of Th2cell (CCR4 + CD4 +) percentage over Th1 cell (CXCR3 + CD4 +) percentage (Th2/Th1) and/or the sum of suppressor/cytotoxic T cells. The total IgE levels and the percentage of PB eosinophils were higher in the severer group than other groups. A shift towards Th2 from Th2/Th1 balanced status may be affected by total counts of suppressor T cells, and the patient with higher Th2/Th1 ratio than balanced status had the more proportion in the severer CSS-CAD group than other groups. The CSS-CAD correlates with total IgE level, PB eosinophil count and a shift towards Th2 immunity from Th2/Th1. So we suggest the Th1/Th2 dysbalance may be affected by the CSS-CAD. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Prevention of experimental diabetes by Uncaria tomentosa extract: Th2 polarization, regulatory T cell preservation or both?

    Science.gov (United States)

    Domingues, Alexandre; Sartori, Alexandrina; Golim, Marjorie Assis; Valente, Ligia Maria Marino; da Rosa, Larissa Camargo; Ishikawa, Larissa Lumi Watanabe; Siani, Antonio Carlos; Viero, Rosa Marlene

    2011-09-01

    Uncaria tomentosa (Willd.) DC (Rubiaceae) is a species native to the Amazon rainforest and surrounding tropical areas that is endowed with immunomodulatory properties and widely used around the world. In this study we investigated the immunomodulatory potential of Uncaria tomentosa (UT) aqueous-ethanol extract on the progression of immune-mediated diabetes. C57BL/6 male mice were injected with MLDS (40 mg/kg) and orally treated with UT at 10-400mg/kg during 21 days. Control groups received MLDS alone or the respective dilution vehicle. Pancreatic mononuclear infiltrate and β-cell insulin content were analyzed by HE and immunohistochemical staining, respectively, and measured by digital morphometry. Lymphocyte immunophenotyping and cytokine production were determined by flow cytometry analysis. Treating the animals with 50-400mg/kg of UT caused a significant reduction in the glycemic levels, as well as in the incidence of diabetes. The morphometric analysis of insulitis revealed a clear protective effect. Animals treated with UT at 400mg/kg presented a higher number of intact islets and a significant inhibition of destructive insulitis. Furthermore, a significant protection against the loss of insulin-secreting presented β-cells was achieved, as observed by a careful immunohistochemical evaluation. The phenotypic analysis indicated that the groups treated with higher doses (100-400mg/kg) presented CD4(+) and CD8(+) T-cell values similar to those observed in healthy animals. These same higher doses also increased the number of CD4(+)CD25(+)Foxp3(+) regulatory T-cells. Moreover, the extract modulated the production of Th1 and Th2, with increased levels of IL-4 and IL-5. The extract was effective to prevent the progression of immune-mediated diabetes by distinct pathways. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  18. Nigella sativa modulates splenocyte proliferation, Th1/Th2 cytokine profile, macrophage function and NK anti-tumor activity.

    Science.gov (United States)

    Majdalawieh, Amin F; Hmaidan, Reem; Carr, Ronald I

    2010-09-15

    Nigella sativa, also known as blackseed, has long been used in traditional medicine for treating various conditions related to the respiratory and gastrointestinal systems as well as different types of cancers. In this study, the potential immunomodulatory effects of Nigella sativa are investigated in light of splenocyte proliferation, macrophage function, and NK anti-tumor activity using BLAB/c and C57/BL6 primary cells. Splenocyte proliferation was assessed by [(3)H]-thymidine incorporation. Griess assay was performed to evaluate NO production by macrophages. ELISA was performed to measure the level of cytokines secreted by splenocytes and macrophages. NK cytotoxic activity against YAC-1 tumor cells was examined by JAM assay. We demonstrate that the aqueous extract of Nigella sativa significantly enhances splenocyte proliferation in a dose-responsive manner. In addition, the aqueous extract of Nigella sativa favors the secretion of Th2, versus Th1, cytokines by splenocytes. The secretion of IL-6, TNFalpha, and NO; key pro-inflammatory mediators, by primary macrophages is significantly suppressed by the aqueous extract of Nigella sativa, indicating that Nigella sativa exerts anti-inflammatory effects in vitro. Finally, experimental evidence indicates that the aqueous extract of Nigella sativa significantly enhances NK cytotoxic activity against YAC-1 tumor cells, suggesting that the documented anti-tumor effects of Nigella sativa may be, at least in part, attributed to its ability to serve as a stimulant of NK anti-tumor activity. Our data present Nigella sativa as a traditionally used herb with potent immunomodulatory, anti-inflammatory, and anti-tumor effects. We anticipate that Nigella sativa ingredients may be employed as effective therapeutic agents in the regulation of diverse immune reactions implicated in various conditions and diseases such as cancer. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  19. Polymorphisms in Th1/Th2 Cytokine Genes, Hormone Replacement Therapy, and Risk of Non-Hodgkin Lymphoma

    International Nuclear Information System (INIS)

    Zhu, Gongjian; Pan, Dongsheng; Zheng, Tongzhang; Lan, Qing; Chen, Xuezhong; Chen, Yingtai; Kim, Christopher; Bi, Xiaofeng; Holford, Theodore; Boyle, Peter; Leaderer, Brian; Chanock, Stephen J.; Rothman, Nathaniel; Zhang, Yawei

    2011-01-01

    We conducted a population-based case–control study in Connecticut women to test the hypothesis that genetic variations in Th1 and Th2 cytokine genes modify the relationship between hormone replacement therapy (HRT) and risk of non-Hodgkin lymphoma (NHL). Compared to women without a history of HRT use, women with a history of HRT use had a significantly decreased risk of NHL if they carried IFNGR2 (rs1059293) CT/TT genotypes (OR = 0.5, 95%CI: 0.3–0.9), IL13 (rs20541) GG genotype (OR = 0.6, 95%CI: 0.4–0.9), and IL13 (rs1295686) CC genotype (OR = 0.6, 95%CI: 0.4–0.8), but not among women who carried IFNGR2 CC, IL13 AG/AA, and IL13CT/TT genotypes. A similar pattern was also observed for B-cell lymphoma but not for T-cell lymphoma. A statistically significant interaction was observed for IFNGR2 (rs1059293 P for interaction = 0.024), IL13(rs20541 P for interaction = 0.005), IL13 (rs1295686 P for interaction = 0.008), and IL15RA (rs2296135 P for interaction = 0.049) for NHL overall; IL13 (rs20541 P for interaction = 0.0009), IL13(rs1295686 P for interaction = 0.0002), and IL15RA (rs2296135 P for interaction = 0.041) for B-cell lymphoma. The results suggest that common genetic variation in Th1/Th pathway genes may modify the association between HRT and NHL risk.

  20. Elevated Levels of Cytokines Associated with Th2 and Th17 Cells in Vitreous Fluid of Proliferative Diabetic Retinopathy Patients.

    Directory of Open Access Journals (Sweden)

    Masaru Takeuchi

    Full Text Available Macrophages are involved in low-grade inflammation in diabetes, and play pathogenic roles in proliferative diabetic retinopathy (PDR by producing proinflammatory cytokines. T cells as well as other cells are also activated by proinflammatory cytokines, and infiltration into the vitreous of patients with PDR has been shown. In this study, we measured helper T (Th cell-related cytokines in the vitreous of PDR patients to define the characteristics of Th-mediated immune responses associated with PDR. The study group consisted of 25 type 2 diabetic patients (25 eyes with PDR. The control group consisted of 27 patients with epiretinal membrane (ERM, 26 patients with idiopathic macular hole (MH, and 26 patients with uveitis associated with sarcoidosis. Vitreous fluid was obtained at the beginning of vitrectomy, and centrifuging for cellular removals was not performed. Serum was also collected from PDR patients. IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble sCD40L, and TNFα in the vitreous and serum samples were measured. Both percent detectable and levels of IL-4, IL-6, IL-17A, IL-21, IL-22, and TNFα in the vitreous were significantly higher than those in the serum in PDR patients. Vitreous levels of these cytokines and IL-31 were significantly higher in PDR than in ERM or MH patients. Vitreous levels of IL-4, IL-17A, IL-22, IL-31, and TNFα in PDR patients were also significantly higher than those of sarcoidosis patients. In PDR patients, vitreous IL-17A level correlated significantly with vitreous levels of IL-22 and IL-31, and especially with IL-4 and TNFα. Although it is unclear whether these cytokines play facilitative roles or inhibitory roles for the progression of PDR, the present study indicated that Th2- and Th17-related immune responses are involved in the pathogenesis of PDR.

  1. A Note on Isolate Domination

    OpenAIRE

    Sahul Hamid, Ismail; Balamurugan, S; Navaneethakrishnan, A

    2016-01-01

    A set $S$ of vertices of a graph $G$ such that $\\left\\langle S\\right\\rangle$ has an isolated vertex is called an \\emph{isolate set} of $G$. The minimum and maximum cardinality of a maximal isolate set are called the \\emph{isolate number} $i_0(G)$ and the \\emph{upper isolate number} $I_0(G)$ respectively. An isolate set that is also a dominating set (an irredundant set) is an $\\emph{isolate dominating set} \\ (\\emph{an isolate irredundant set})$. The \\emph{isolate domination number} $\\gamma_0(G...

  2. Domination criticality in product graphs

    Directory of Open Access Journals (Sweden)

    M.R. Chithra

    2015-07-01

    Full Text Available A connected dominating set is an important notion and has many applications in routing and management of networks. Graph products have turned out to be a good model of interconnection networks. This motivated us to study the Cartesian product of graphs G with connected domination number, γc(G=2,3 and characterize such graphs. Also, we characterize the k−γ-vertex (edge critical graphs and k−γc-vertex (edge critical graphs for k=2,3 where γ denotes the domination number of G. We also discuss the vertex criticality in grids.

  3. Dominantly inherited cystoid macular edema.

    Science.gov (United States)

    Fishman, G A; Goldberg, M F; Trautmann, J C

    1979-01-01

    Four patients of Greek ancestry had dominantly inherited cystoid macular edema. Characteristics of this syndrome include the following: an early onset and prolonged course of cystoid changes in the macula, followed by atrophy of the macula in later stages. Some patients also show leakage of fluorescein from the optic disc capillaries, subnormal EOG Lp/Dt ratios, elevated rod dark adaptation thresholds, red-green and blue-yellow color deficiencies, normal ERG findings, hyperopia, peripheral pigmentary retinopathy, and vitreous opacities. Dominantly inherited cystoid macular edema is a distinct genetic trait among the dominantly inherited macular dystrophies.

  4. Human mammary progenitor cell fate decisions are productsof interactions with combinatorial microenvironments

    DEFF Research Database (Denmark)

    LaBarge, Mark A.; Nelson, Celeste M.; Villadsen, René

    2009-01-01

    factors, ECM, and other cells, as well as physical properties of the ECM. To understand regulation of fate decisions, therefore, would require a means of understanding carefully choreographed combinatorial interactions. Here we used microenvironment protein microarrays to functionally identify...

  5. Activation of human basophils by combined toll-like receptor- and FcεRI-triggering can promote Th2 skewing of naive T helper cells.

    Science.gov (United States)

    Suurmond, Jolien; Stoop, Jeroen N; Rivellese, Felice; Bakker, Aleida M; Huizinga, Tom W J; Toes, René E M

    2014-02-01

    Basophils are mostly known for their involvement in allergic reactions. Recent studies in mice indicate a role for basophils in the induction of adaptive immunity, especially T helper 2 (Th2) responses. Therefore, it would be highly important to understand how basophils respond to pathogen-associated molecules, such as ligands for toll-like receptors (TLRs), and if the basophils could promote Th2 responses via these stimuli. To this end, the activation of basophils via TLRs in combination with activation via IgE was studied, as well as its effect on T helper cell skewing. Using quantitative PCR, we demonstrated the presence of mRNA for TLRs 1-8 in human basophils. Basophils responded to TLR triggering with differential cytokine production, but not with degranulation. Simultaneous triggering of TLRs and IgE led to synergy in production of IL-4, IL-8, IL-13, and RANTES. Furthermore, the synergistic effects on basophils mediated by IgE and TLR-4 triggering allowed robust Th2 skewing upon activation of naïve human CD4⁺ T cells. Our data show that human basophils respond to TLR ligands in synergy with IgE-mediated activation and that the cytokines produced can promote Th2 differentiation. These results indicate a role for basophils in the regulation of T-cell responses in humans. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. In vitro Th1 and Th2 cell polarization is severely influenced by the initial ratio of naïve and memory CD4+ T cells

    DEFF Research Database (Denmark)

    Blom, Lars; Poulsen, Lars K.

    2013-01-01

    Robust in vitro systems are important in elucidating mechanisms regarding the heterogenetic nature of in vivo immune responses and contribute with knowledge to design good in vivo experiments. In this study, we show that initial Th1 and in particular Th2 polarization was negatively influenced by ...

  7. Nuclear Factor of Activated T Cells Regulates the Expression of Interleukin-4 in Th2 Cells in an All-or-none Fashion*

    Science.gov (United States)

    Köck, Juliana; Kreher, Stephan; Lehmann, Katrin; Riedel, René; Bardua, Markus; Lischke, Timo; Jargosch, Manja; Haftmann, Claudia; Bendfeldt, Hanna; Hatam, Farahnaz; Mashreghi, Mir-Farzin; Baumgrass, Ria; Radbruch, Andreas; Chang, Hyun-Dong

    2014-01-01

    Th2 memory lymphocytes have imprinted their Il4 genes epigenetically for expression in dependence of T cell receptor restimulation. However, in a given restimulation, not all Th cells with a memory for IL-4 expression express IL-4. Here, we show that in reactivated Th2 cells, the transcription factors NFATc2, NF-kB p65, c-Maf, p300, Brg1, STAT6, and GATA-3 assemble at the Il4 promoter in Th2 cells expressing IL-4 but not in Th2 cells not expressing it. NFATc2 is critical for assembly of this transcription factor complex. Because NFATc2 translocation into the nucleus occurs in an all-or-none fashion, dependent on complete dephosphorylation by calcineurin, NFATc2 controls the frequencies of cells reexpressing Il4, translates analog differences in T cell receptor stimulation into a digital decision for Il4 reexpression, and instructs all reexpressing cells to express the same amount of IL-4. This analog-to-digital conversion may be critical for the immune system to respond to low concentrations of antigens. PMID:25037220

  8. Characterization and Function of the Inflammatory Response to Infection by a Gastrointestinal Nematode Parasite: New Insights into Protective Th2 Responses

    Science.gov (United States)

    2006-01-01

    identifies macrophages as important effector cells in protective Th2 responses, providing a possible explanation for the evolution of their...expression of chitinases and chitinase-like genes suggests a potential effector mechanism, as some helminth parasites feature a chitin cuticle that...M.B. Ascaris lumbricoides aggregation in relation to child growth status, delayed cutaneous hypersensitivity, and plant anthelmintic use in

  9. The Th1/Th2/Th17/Treg paradigm induced by stachydrine hydrochloride reduces uterine bleeding in RU486-induced abortion mice.

    Science.gov (United States)

    Li, Xia; Wang, Bin; Li, Yuzhu; Wang, Li; Zhao, Xiangzhong; Zhou, Xianbin; Guo, Yuqi; Jiang, Guosheng; Yao, Chengfang

    2013-01-09

    The Th1/Th2/Th17/Treg paradigm plays an important role in achieving maternal-fetal immunotolerance and participates in RU486-induced abortion. Excessive uterine bleeding is the most common side effect of RU486-induced abortion; however, its etiopathogenesis has not been fully understood. Therefore, elucidating the correlation between the Th1/Th2/Th17/Treg paradigm and the volume of uterine bleeding may offer novel therapeutic target for reducing uterine bleeding in RU486-induced abortion. Leonurus sibiricus has been used in clinics to reduce postpartum hemorrhage with low toxicity and high efficiency; however, the effective constituents and therapeutic mechanism have not been described. Stachydrine hydrochloride is the main constituent of L. sibiricus, therefore L. sibiricus is regarded as a candidate for reducing uterine bleeding in RU486-induced abortion mice by regulating the Th1/Th2/Th17/Treg paradigm. The purpose of this study was to determine the Th1/Th2/Th17/Treg paradigm in uterine bleeding of RU486-induced abortion mice and to elucidate the immunopharmacologic effects of stachydrine hydrochloride on inducing the Th1/Th2/Th17/Treg paradigm in reducing the uterine bleeding volume in RU486-induced abortion mice. To investigate the Th1/Th2/Th17/Treg paradigm in uterine bleeding during RU486-induced abortion mice, pregnant BALB/c mice were treated with high- and low-dose RU486 (1.5mg/kg and 0.9 mg/kg, respectively), and the serum progesterone (P(4)) protein level, uterine bleeding volume, and proportions of Th1/Th2/Th17/Treg cells in mice at the maternal-fetal interface were detected by ELISA assay, alkaline hematin photometric assay, and flow cytometry, respectively. To determine the regulatory effect of stachydrine hydrochloride on the Th1/Th2/Th17/Treg paradigm in vitro, splenocytes of non-pregnant mice were separated and treated with P(4,) RU486, and/or stachydrine hydrochloride (10(-5)M, 10(-4)M, and 10(-3)M, respectively). The proportions of Th1/Th2/Th17

  10. Chronic Pseudomonas aeruginosa lung infection is more severe in Th2 responding BALB/c mice compared to Th1 responding C3H/HeN mice

    DEFF Research Database (Denmark)

    Moser, C; Johansen, H K; Song, Z

    1997-01-01

    model of this infection was established in two strains of mice: C3H/HeN and BALB/c, generally known as Th1 and Th2 responders, respectively, which were challenged with alginate-embedded P. aeruginosa. Mortality was significantly lower in C3H/HeN compared to BALB/c mice (p

  11. Nuclear factor of activated T cells regulates the expression of interleukin-4 in Th2 cells in an all-or-none fashion.

    Science.gov (United States)

    Köck, Juliana; Kreher, Stephan; Lehmann, Katrin; Riedel, René; Bardua, Markus; Lischke, Timo; Jargosch, Manja; Haftmann, Claudia; Bendfeldt, Hanna; Hatam, Farahnaz; Mashreghi, Mir-Farzin; Baumgrass, Ria; Radbruch, Andreas; Chang, Hyun-Dong

    2014-09-26

    Th2 memory lymphocytes have imprinted their Il4 genes epigenetically for expression in dependence of T cell receptor restimulation. However, in a given restimulation, not all Th cells with a memory for IL-4 expression express IL-4. Here, we show that in reactivated Th2 cells, the transcription factors NFATc2, NF-kB p65, c-Maf, p300, Brg1, STAT6, and GATA-3 assemble at the Il4 promoter in Th2 cells expressing IL-4 but not in Th2 cells not expressing it. NFATc2 is critical for assembly of this transcription factor complex. Because NFATc2 translocation into the nucleus occurs in an all-or-none fashion, dependent on complete dephosphorylation by calcineurin, NFATc2 controls the frequencies of cells reexpressing Il4, translates analog differences in T cell receptor stimulation into a digital decision for Il4 reexpression, and instructs all reexpressing cells to express the same amount of IL-4. This analog-to-digital conversion may be critical for the immune system to respond to low concentrations of antigens. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Selective recruitment of Th2-type cells and evasion from a cytotoxic immune response mediated by viral macrophage inhibitory protein-II.

    Science.gov (United States)

    Weber, K S; Gröne, H J; Röcken, M; Klier, C; Gu, S; Wank, R; Proudfoot, A E; Nelson, P J; Weber, C

    2001-08-01

    The viral CC chemokine macrophage inhibitory protein-II (vMIP-II) encoded by human herpes virus 8 (HHV-8) binds to multiple chemokine receptors, however, its ability to control the initial recruitment of specific leukocyte subtypes from the peripheral circulation has not been fully clarified. Here we show that vMIP-II blocks the firm arrest and transmigration of monocytes or Th1-like T lymphocytes triggered by RANTES immobilized on activated human microvascular endothelium (HMVEC) under flow conditions. The internalization of the receptors CCR1 and CCR5 that mediate arrest and transmigration of these cells in response to RANTES was prevented by vMIP-II, supporting its role as an antagonist of CCR1 and CCR5. In contrast, vMIP-II triggered the firm arrest of eosinophils and Th2-like T cells by engaging CCR3, as confirmed by its down-regulation. Immunohistochemical analysis of HHV-8-associated Kaposi's sarcoma lesions marked by vMIP-II expression and mononuclear cell infiltration revealed a predominance of Th2-type CCR3(+) lymphocytes over Th1-type CXCR3(+)/CCR5(+) leukocytes, indicating that as a CCR3 agonist vMIP-II can drive a Th2-type immune response in vivo. Thus, our data provide evidence for a immunomodulatory role of vMIP-II in directing inflammatory cell recruitment away from a Th1-type towards a Th2-type response and thereby facilitating evasion from cytotoxic reactions.

  13. The inflammatory milieu within the pancreatic cancer microenvironment correlates with clinicopathologic parameters, chemoresistance and survival

    OpenAIRE

    Delitto, Daniel; Black, Brian S.; Sorenson, Heather L.; Knowlton, Andrea E.; Thomas, Ryan M.; Sarosi, George A.; Moldawer, Lyle L.; Behrns, Kevin E.; Liu, Chen; George, Thomas J.; Trevino, Jose G.; Wallet, Shannon M.; Hughes, Steven J.

    2015-01-01

    Background The tumor microenvironment impacts pancreatic cancer (PC) development, progression and metastasis. How intratumoral inflammatory mediators modulate this biology remains poorly understood. We hypothesized that the inflammatory milieu within the PC microenvironment would correlate with clinicopathologic findings and survival. Methods Pancreatic specimens from normal pancreas (n = 6), chronic pancreatitis (n = 9) and pancreatic adenocarcinoma (n = 36) were homogenized immediately upon...

  14. Phenotypic Mapping of The Chicken Embryonic Thymic Microenvironment Developing Within an Organ Culture System

    OpenAIRE

    Davidson, Natalie J.; Boyd, Richard L.

    1993-01-01

    The chicken thymic microenvironment, as it developed in an embryonic thymus organ culture system, was phenotypically mapped using a panel of mAb defining both epithelial and nonepithelial stromal cell antigens. We have previously reported that thymocyte proliferation and differentiation will proceed for up to 6–8 days in thymus organ culture, hence demonstrating the functional integrity of the thymic microenvironment in vitro. During this time, the stromal component reflected that of the norm...

  15. Aerobic glycolysis and high level of lactate in cancer metabolism and microenvironment

    Directory of Open Access Journals (Sweden)

    Bo Jiang

    2017-03-01

    Full Text Available Metabolic abnormalities is a hallmark of cancer. About 100 years ago, Nobel laureate Otto Heinrich Warburg first described high rate of glycolysis in cancer cells. Recently more and more novel opinions about cancer metabolism supplement to this hypothesis, consist of glucose uptake, lactic acid generation and secretion, acidification of the microenvironment and cancer immune evasion. Here we briefly review metabolic pathways generating lactate, and discuss the function of higher lactic acid in cancer microenvironments.

  16. The Role of Hypoxia in the Tumor Microenvironment: Implications for Ovarian Cancer Therapy

    Science.gov (United States)

    2017-07-01

    kit (Rankin et al., 2012). Tumor sections will be stained and quantified for CD31, an endothelial cell marker . The number of CD31 positive vessels...AWARD NUMBER: W81XWH-15-1-0097 TITLE: The Role of Hypoxia in the Tumor Microenvironment: Implications for Ovarian Cancer Therapy PRINCIPAL...SUBTITLE 5a. CONTRACT NUMBER 0097W81XW 0097The Role of Hypoxia in the Tumor Microenvironment: Implications for Ovarian Cancer Therapy

  17. Contribution of various microenvironments to the daily personal exposure to ultrafine particles

    DEFF Research Database (Denmark)

    Bekö, Gabriel; Kjeldsen, Birthe Uldahl; Olsen, Yulia

    2015-01-01

    occurring in various microenvironments (residence, during active and passive transport, other indoor and outdoor environments) to the total daily exposure. On average, the fractional contribution of each microenvironment to the daily integrated personal exposure roughly corresponded to the fractions......, compared to the GPS. These results may indicate limitations of using diaries, but also possible inaccuracy and miss-classification in the GPS data. (C) 2015 Elsevier Ltd. All rights reserved....

  18. Basal Cell Carcinoma in Gorlin's Patients: a Matter of Fibroblasts-Led Protumoral Microenvironment?

    Science.gov (United States)

    Gache, Yannick; Brellier, Florence; Rouanet, Sophie; Al-Qaraghuli, Sahar; Goncalves-Maia, Maria; Burty-Valin, Elodie; Barnay, Stéphanie; Scarzello, Sabine; Ruat, Martial; Sevenet, Nicolas; Avril, Marie-Françoise; Magnaldo, Thierry

    2015-01-01

    Basal cell carcinoma (BCC) is the commonest tumor in human. About 70% sporadic BCCs bear somatic mutations in the PATCHED1 tumor suppressor gene which encodes the receptor for the Sonic Hedgehog morphogen (SHH). PATCHED1 germinal mutations are associated with the dominant Nevoid Basal Cell Carcinoma Syndrome (NBCCS), a major hallmark of which is a high susceptibility to BCCs. Although the vast majority of sporadic BCCs arises exclusively in sun exposed skin areas, 40 to 50% BCCs from NBCCS patients develop in non photo-exposed skin. Since overwhelming evidences indicate that microenvironment may both be modified by- and influence the- epithelial tumor, we hypothesized that NBCCS fibroblasts could contribute to BCCs in NBCCS patients, notably those developing in non photo-exposed skin areas. The functional impact of NBCCS fibroblasts was then assessed in organotypic skin cultures with control keratinocytes. Onset of epidermal differentiation was delayed in the presence of primary NBCCS fibroblasts. Unexpectedly, keratinocyte proliferation was severely reduced and showed high levels of nuclear P53 in both organotypic skin cultures and in fibroblast-led conditioning experiments. However, in spite of increased levels of senescence associated β-galactosidase activity in keratinocytes cultured in the presence of medium conditioned by NBCCS fibroblasts, we failed to observe activation of P16 and P21 and then of bona fide features of senescence. Constitutive extinction of P53 in WT keratinocytes resulted in an invasive phenotype in the presence of NBCCS fibroblasts. Finally, we found that expression of SHH was limited to fibroblasts but was dependent on the presence of keratinocytes. Inhibition of SHH binding resulted in improved epidermal morphogenesis. Altogether, these data suggest that the repertoire of diffusible factors (including SHH) expressed by primary NBCCS fibroblasts generate a stress affecting keratinocytes behavior and epidermal homeostasis. Our findings

  19. Basal Cell Carcinoma in Gorlin's Patients: a Matter of Fibroblasts-Led Protumoral Microenvironment?

    Directory of Open Access Journals (Sweden)

    Yannick Gache

    Full Text Available Basal cell carcinoma (BCC is the commonest tumor in human. About 70% sporadic BCCs bear somatic mutations in the PATCHED1 tumor suppressor gene which encodes the receptor for the Sonic Hedgehog morphogen (SHH. PATCHED1 germinal mutations are associated with the dominant Nevoid Basal Cell Carcinoma Syndrome (NBCCS, a major hallmark of which is a high susceptibility to BCCs. Although the vast majority of sporadic BCCs arises exclusively in sun exposed skin areas, 40 to 50% BCCs from NBCCS patients develop in non photo-exposed skin. Since overwhelming evidences indicate that microenvironment may both be modified by- and influence the- epithelial tumor, we hypothesized that NBCCS fibroblasts could contribute to BCCs in NBCCS patients, notably those developing in non photo-exposed skin areas. The functional impact of NBCCS fibroblasts was then assessed in organotypic skin cultures with control keratinocytes. Onset of epidermal differentiation was delayed in the presence of primary NBCCS fibroblasts. Unexpectedly, keratinocyte proliferation was severely reduced and showed high levels of nuclear P53 in both organotypic skin cultures and in fibroblast-led conditioning experiments. However, in spite of increased levels of senescence associated β-galactosidase activity in keratinocytes cultured in the presence of medium conditioned by NBCCS fibroblasts, we failed to observe activation of P16 and P21 and then of bona fide features of senescence. Constitutive extinction of P53 in WT keratinocytes resulted in an invasive phenotype in the presence of NBCCS fibroblasts. Finally, we found that expression of SHH was limited to fibroblasts but was dependent on the presence of keratinocytes. Inhibition of SHH binding resulted in improved epidermal morphogenesis. Altogether, these data suggest that the repertoire of diffusible factors (including SHH expressed by primary NBCCS fibroblasts generate a stress affecting keratinocytes behavior and epidermal homeostasis

  20. Social Dominance and Sexual Orientation

    OpenAIRE

    Dickins, Thomas E.; Sergeant, Mark J.T.

    2008-01-01

    Heterosexual males are reported to display higher levels of physical aggression and lower levels of empathy than homosexual males. A characteristic linked to both aggression and empathy is social dominance orientation (SDO). A significant sex difference has been reported for SDO, with heterosexual males scoring higher than heterosexual females. The precise relationship between dominance and aggression is currently contested. Given the association between SDO, aggression and empathy, and the d...

  1. Upregulation of Tim-3 on CD4(+) T cells is associated with Th1/Th2 imbalance in patients with allergic asthma.

    Science.gov (United States)

    Tang, Fei; Wang, Fukun; An, Liyun; Wang, Xianling

    2015-01-01

    T cell Ig and mucin domain-containing molecule-3 (Tim-3) is a negative regulator preferentially expressed on Th1 cells. Allergic asthma is a clinical syndrome well characterized by Th1/Th2 imbalance. To investigate the role of Tim-3 in the pathogenesis of asthma and its relationship with Th1/Th2 imbalance, a total of 40 patients with allergic asthma and 40 healthy controls were enrolled. Expression of Tim-3 and Th1/Th2 imbalance as well as the relationship between them was analyzed by flow cytometry and real-time PCR. Peripheral blood mononuclear cells (PBMCs) were cultured in vitro and anti-Tim-3 was used to block Tim-3 signaling; Th1/Th2 cytokines in the culture supernatant were detected by enzyme linked immunosorbent assay (ELISA). CD4(+) T cells and B cells were sorted and co-cultured in vitro, and anti-Tim-3 was used to block Tim-3 signaling; Total IgG/IgE in the culture supernatant was detected by ELISA. The mRNA level of T-bet and IFN-γ were significantly decreased in allergic asthma patients, while GATA-3 and IL-4 were significantly increased. Expression of Tim-3 on CD4(+) T cells was much higher in allergic asthma patients and it was negatively correlated with T-bet/GATA-3 ratio or IFN-γ/IL-4 ratio. Blocking of Tim-3 significantly increased Th1 cytokines (TNF-α and IFN-γ) and decreased Th2 cytokines (IL-4, IL-5, IL-13) in the culture supernatant of PBMCs. Blocking of Tim-3 dramatically reduced the production of IgG and IgE in the co-culture supernatant of CD4(+) T cells and B cells. In conclusion, Tim-3 was up-regulated in allergic asthma patients and related with the Th1/Th2 imbalance. Blocking of Tim-3 may be of therapeutic benefit by enhancing the Th1 cytokines response, down-regulating the Th2 cytokines response, and reducing IgG/IgE production.

  2. Effects of Acute Low-Dose Exposure to the Chlorinated Flame Retardant Dechlorane 602 and Th1 and Th2 Immune Responses in Adult Male Mice.

    Science.gov (United States)

    Feng, Yu; Tian, Jijing; Xie, Heidi Qunhui; She, Jianwen; Xu, Sherry Li; Xu, Tuan; Tian, Wenjing; Fu, Hualing; Li, Shuaizhang; Tao, Wuqun; Wang, Lingyun; Chen, Yangsheng; Zhang, Songyan; Zhang, Wanglong; Guo, Tai L; Zhao, Bin

    2016-09-01

    Although the chlorinated flame retardant Dechlorane (Dec) 602 has been detected in food, human blood, and breast milk, there is limited information on potential health effects, including possible immunotoxicity. We determined the immunotoxic potential of Dec 602 in mice by examining the expression of phenotypic markers on thymocyte and splenic lymphocyte subsets, Th1/Th2 transcription factors, and the production of cytokines and antibodies. Adult male C57BL/6 mice were orally exposed to environmentally relevant doses of Dec 602 (1 and 10 μg/kg body weight per day) for 7 consecutive days. Thymocyte and splenic CD4 and CD8 subsets and splenocyte apoptosis were examined by flow cytometric analysis. Cytokine expression was measured at both the mRNA and the protein levels. Levels of the transcription factors Th1 (T-bet and STAT1) and Th2 (GATA3) were determined using quantitative real-time polymerase chain reaction (qPCR). Serum levels of immunoglobulins IgG1, IgG2a, IgG2b and IgE were measured by enzyme-linked immunosorbent assay (ELISA). Splenic CD4+ and CD8+ T cell subsets were decreased compared with vehicle controls, and apoptosis was significantly increased in splenic CD4+ T cells. Expression (mRNA and protein) of Th2 cytokines [interleukin (IL)-4, IL-10, and IL-13] increased, and that of Th1 cytokines [IL-2, interferon (IFN)-γ and tumor necrosis factor (TNF)-α] decreased. The Th2 transcriptional factor GATA3 increased, whereas the Th1 transcriptional factors T-bet and STAT1 decreased. As additional indicators of the Th2-Th1 imbalance, production of IgG1 was significantly increased, whereas IgG2a was reduced. To our knowledge, we are the first to report evidence of the effects of Dec 602 on immune function in mice, with findings indicating that Dec 602 exposure favored Th2 responses and reduced Th1 function. Feng Y, Tian J, Xie HQ, She J, Xu SL, Xu T, Tian W, Fu H, Li S, Tao W, Wang L, Chen Y, Zhang S, Zhang W, Guo TL, Zhao B. 2016. Effects of acute low

  3. A note on isolate domination

    Directory of Open Access Journals (Sweden)

    Ismail Sahul Hamid

    2016-04-01

    Full Text Available A set $S$ of vertices of a graph $G$ such that $\\left\\langle S\\right\\rangle$ has an isolated vertex is called an \\emph{isolate set} of $G$. The minimum and maximum cardinality of a maximal isolate set are called the \\emph{isolate number} $i_0(G$ and the \\emph{upper isolate number} $I_0(G$ respectively. An isolate set that is also a dominating set (an irredundant set is an $\\emph{isolate dominating set} \\ (\\emph{an isolate irredundant set}$. The \\emph{isolate domination number} $\\gamma_0(G$ and the \\emph{upper isolate domination number} $\\Gamma_0(G$ are respectively the minimum and maximum cardinality of a minimal isolate dominating set while the \\emph{isolate irredundance number} $ir_0(G$ and the \\emph{upper isolate irredundance number} $IR_0(G$ are the minimum and maximum cardinality of a maximal isolate irredundant set of $G$. The notion of isolate domination was introduced in \\cite{sb} and the remaining were introduced in \\cite{isrn}. This paper further extends a study of these parameters.   

  4. Cell microenvironment engineering and monitoring for tissue engineering and regenerative medicine: the recent advances.

    Science.gov (United States)

    Barthes, Julien; Özçelik, Hayriye; Hindié, Mathilde; Ndreu-Halili, Albana; Hasan, Anwarul; Vrana, Nihal Engin

    2014-01-01

    In tissue engineering and regenerative medicine, the conditions in the immediate vicinity of the cells have a direct effect on cells' behaviour and subsequently on clinical outcomes. Physical, chemical, and biological control of cell microenvironment are of crucial importance for the ability to direct and control cell behaviour in 3-dimensional tissue engineering scaffolds spatially and temporally. In this review, we will focus on the different aspects of cell microenvironment such as surface micro-, nanotopography, extracellular matrix composition and distribution, controlled release of soluble factors, and mechanical stress/strain conditions and how these aspects and their interactions can be used to achieve a higher degree of control over cellular activities. The effect of these parameters on the cellular behaviour within tissue engineering context is discussed and how these parameters are used to develop engineered tissues is elaborated. Also, recent techniques developed for the monitoring of the cell microenvironment in vitro and in vivo are reviewed, together with recent tissue engineering applications where the control of cell microenvironment has been exploited. Cell microenvironment engineering and monitoring are crucial parts of tissue engineering efforts and systems which utilize different components of the cell microenvironment simultaneously can provide more functional engineered tissues in the near future.

  5. Optimization of the tumor microenvironment and nanomedicine properties simultaneously to improve tumor therapy.

    Science.gov (United States)

    Zhang, Bo; Shi, Wei; Jiang, Ting; Wang, Lanting; Mei, Heng; Lu, Heng; Hu, Yu; Pang, Zhiqing

    2016-09-20

    Effective delivery of nanomedicines to tumor tissues depends on both the tumor microenvironment and nanomedicine properties. Accordingly, tumor microenvironment modification or advanced design of nanomedicine was emerging to improve nanomedicine delivery to tumors. However, few studies have emphasized the necessity to optimize the tumor microenvironment and nanomedicine properties simultaneously to improve tumor treatment. In the present study, imatinib mesylate (IMA) was used to normalize the tumor microenvironment including platelet-derived growth factor receptor-β expression inhibition, tumor vessel normalization, and tumor perfusion improvement as demonstrated by immunofluorescence staining. In addition, the effect of tumor microenvironment normalization on tumor delivery of nanomedicines with different sizes was carefully investigated. It was shown that IMA treatment significantly reduced the accumulation of nanoparticles (NPs) around 110 nm but enhanced the accumulation of micelles around 23 nm by in vivo fluorescence imaging experiment. Furthermore, IMA treatment limited the distribution of NPs inside tumors but increased that of micelles with a more homogeneous pattern. Finally, the anti-tumor efficacy study displayed that IMA pretreatment could significantly increase the therapeutic effects of paclitaxel-loaded micelles. All-together, a new strategy to improve nanomedicine delivery to tumor was provided by optimizing both nanomedicine size and the tumor microenvironment simultaneously, and it will have great potential in clinics for tumor treatment.

  6. MR-Visible Lipids and the Tumor Microenvironment

    Science.gov (United States)

    Delikatny, E. James; Chawla, Sanjeev; Leung, Daniel-Joseph; Poptani, Harish

    2013-01-01

    MR-visible lipids or mobile lipids are defined as lipids that are observable using proton magnetic resonance spectroscopy in cells and in tissues. These MR-visible lipids are composed of triglycerides and cholesterol esters that accumulate in intracellular neutral lipid droplets, where their MR visibility is conferred as a result of the increased molecular motion available in this unique physical environment. This review will discuss factors that lead to the biogenesis of MR-visible lipids in cancer cells and in other cell types such as immune cells and fibroblasts. We focus on the accumulations of mobile lipids that are inducible in cultured cells by a number of stresses, including culture conditions and in response to activating stimuli or apoptotic cell death induced by anticancer drugs. This is compared with animal tumor models, where increases in mobile lipids are observed in response to chemo and radiotherapy, and to human tumors where mobile lipids are observed predominantly in high-grade brain tumors and in regions of necrosis. Conducive conditions for mobile lipid formation in the tumor microenvironment will be discussed including low pH, oxygen availability and the presence of inflammatory cells. It is concluded that MR-visible lipids appear in cancer cells and human tumors as a stress response. Mobile lipids stored as neutral lipid droplets may play a role in detoxification of the cell or act as an alternate energy source, especially in cancer cells, which often grow in ischemic/hypoxic environments. The role of MR-visible lipids in cancer diagnosis and assessment of treatment response both in animal models of cancer as well as human brain tumors will also be discussed. Although technical limitations exist in the accurate detection of intratumoral mobile lipids, early increases in mobile lipids after therapeutic interventions may be used as a potential biomarker for assessing treatment response in cancer. PMID:21538631

  7. WE-E-BRE-12: Tumor Microenvironment Dynamics Following Radiation

    International Nuclear Information System (INIS)

    Campos, D; Niles, D; Adamson, E; Torres, A; Kissick, M; Eliceiri, K; Kimple, R

    2014-01-01

    Purpose: This work aims to understand the radiation-induced interplay between tumor oxygenation and metabolic activity. These dynamics can potentially serve as biomarkers in assessing treatment response allowing for patient-specific adaptive radiotherapy. Methods: Using patient-derived xenografts of head and neck cancer we assessed tumor oxygenation via fiber-optic probe monitored hemoglobin saturation and Blood Oxygen Level Dependent (BOLD) MRI. Measurements were taken before and after a 10 Gy dose of radiation. Changes in metabolic activity were measured via Fluorescence Lifetime IMaging (FLIM) with the appropriate controls following a 10 Gy dose of radiation. FLIM can non-invasively monitor changes in fluorescence in response to the microenvironment including being able to detect free and bound states of the intrinsically fluorescent metabolite NADH (Nicotinamide Adenine Dinucleotide). With this information FLIM can accurately quantify the metabolic state of cells that have been radiated. To model the observed changes, a two-compartment, source-sink simulation relating hemoglobin saturation and metabolic activity was performed using MATLAB. Results: Hemoglobin saturation as measured by interstitial probe and BOLD-MRI decreased by 30% within 15 minutes following radiation. FLIM demonstrated a decrease in the mean fluorescence lifetime of NADH by 100 ps following 10 Gy indicating a shift towards glycolytic pathways. Simulation of radiation-induced alterations in tumor oxygenation demonstrated that these changes can be the result of changes in either vasculature or metabolic activity. Conclusion: Radiation induces significant changes in hemoglobin saturation and metabolic activity. These alterations occur on time scales approximately the duration of common radiation treatments. Further understanding these dynamics has important implications with regard to improvement of therapy and biomarkers of treatment response

  8. On the Mechanism Determining the Th1/Th2 Phenotype of an Immune Response, and its Pertinence to Strategies for the Prevention, and Treatment, of Certain Infectious Diseases

    Science.gov (United States)

    Bretscher, P A

    2014-01-01

    It is well recognized that the physiological/pathological consequences of an immune response, against a foreign or a self-antigen, are often critically dependent on the class of immunity generated. Here we focus on how antigen interacts with the cells of the immune system to determine whether antigen predominantly generates Th1 or Th2 cells. We refer to this mechanism as the ‘decision criterion’ controlling the Th1/Th2 phenotype of the immune response. A plausible decision criterion should account for the variables of immunization known to affect the Th1/Th2 phenotype of the ensuing immune response. Documented variables include the nature of the antigen, in terms of its degree of foreignness, the dose of antigen and the time after immunization at which the Th1/Th2 phenotype of the immune response is assessed. These are quantitative variables made at the level of the system. In addition, the route of immunization is also critical. I describe a quantitative hypothesis as to the nature of the decision criterion, referred to as the Threshold Hypothesis. This hypothesis accounts for the quantitative variables of immunization known to affect the Th1/Th2 phenotype of the immune response generated. I suggest and illustrate how this is not true of competing, contemporary hypotheses. I outline studies testing predictions of the hypothesis and illustrate its potential utility in designing strategies to prevent or treat medical situations where a predominant Th1 response is required to contain an infection, such as those caused by HIV-1 and by Mycobacterium tuberculosis, or to contain cancers. PMID:24684592

  9. [Study on the correlation of the effect of entecavir on Th1/Th2 cytokines level in the treatment of chronic hepatitis].

    Science.gov (United States)

    Li, L; Jing, Y B; Liu, J; Wang, C L; Liu, B

    2017-08-20

    Objective: To explore the expression level of peripheral blood Th1/Th2 type cytokines of chronic hepatitis b (CHB) patients in the entecavir (ETV) antiviral treatment, analyze the relationship between various cytokines, and the correlation among of cytokines and HBV DNA loads. Methods: Luminex Liquid Chip Technology was applied to detect the peripheral blood Th1/Th2 type cytokines expression level of CHB patients; At the same time, liver function was detected by Fully Automatic Biochemical Analyzer; HBV DNA loads were detected by PCR Method; Hepatitis b virology markers were detected by Chemiluminescence Method. F-test and Pearson correlation analysis were used for statistical analysis. Results: Before ETV antiviral treatment, peripheral blood Th1 cytokines IFN gamma expression level in patients with CHB increased significantly ( P = 0.010) compared with the healthy control group while TNF alpha expression level having no statistically significant difference ( P = 0.095); Th2 type cytokines IL-4, IL-6, IL-10 levels decreased obviously ( P = 0.039, P = 0.014, P = 0.026) compared with those in the control group. After 48 weeks of treatment, Th1 cytokines IFN gamma and TNF alpha expression levels were reduced significantly (19.2±5.03 pg/ml vs 24.69±6.51 pg/ml, and 6.09±4.99 pg/ml vs 9.50±7.34 pg/ml, P Th1/Th2 type cytokines. And there was no correlation between the various cytokines and HBV DNA loads in patients with CHB. Conclusion: ETV can not only inhibit HBV DNA replication, reducing HBV DNA loads, but also contribute to regulate Th1/Th2 type cytokines expression level in patients with CHB, but there was no correlation between the levels of various cytokines, various cytokines and HBV DNA loads.

  10. Effect of Intravenous immunoglobulin on Th1 and Th2 lymphocytes and improvement of pregnancy outcome in recurrent pregnancy loss (RPL).

    Science.gov (United States)

    Ahmadi, Majid; Abdolmohammadi-Vahid, Samaneh; Ghaebi, Mahnaz; Aghebati-Maleki, Leili; Afkham, Amir; Danaii, Shahla; Abdollahi-Fard, Sedigheh; Heidari, Lida; Jadidi-Niaragh, Farhad; Younesi, Vahid; Nouri, Mohammad; Yousefi, Mehdi

    2017-08-01

    Women with elevated natural killer (NK) cell frequency and function during pregnancy, suffer from recurrent pregnancy loss (RPL). In the present study, the possible effect of intravenous immunoglobulin (IVIG) administration on Th1 and Th2 cell frequency, cytokine secretion, and expression of transcription factors is compared between RPL patients and control group. Totally, 44 women with a history of RPL (32 women as treated group and 12 as control group) were enrolled in the study. The frequency of Th1 and Th2 lymphocytes, the expression of transcription factors related to these cells and the serum levels of associated cytokines were assessed by flowcytometry, real-time PCR and ELISA, respectively. All, assessments were performed both before and after treatment with IVIG. A significant reduction in Th1 lymphocyte frequency, transcription factor expression and cytokine levels were observed in IVIG-treated group, while all the above parameters indicated a significant increase for Th2 lymphocytes. Th1/Th2 ratio decreased significantly (p value<0.0001) at the end of treatment and 28 out of 32 (87.5%) women in IVIG-treated group had live birth in comparison with 5 out of 12 (41.6%) in untreated group. IVIG administration proves to be an efficient therapeutic strategy which is able to enhance the success rate of pregnancy through a shift in Th2 responses. Furthermore, IVIG presents efficacy for the treatment of reproduction failures especially in subjects with immune cell abnormalities and increased NK cell level and function. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. [Relationship of reduced lung function with Th1/Th2 polarization, STAT4/6 expression in rats of chronic obstructive pulmonary disease].

    Science.gov (United States)

    Wang, Chengyang; Li, Zegeng

    2013-12-01

    To study the correlations between lung function and Th1/Th2 polarization, signal transducer and activator of transcription (STAT) proteins in rats of chronic obstructive pulmonary disease (COPD). Sixty rats were randomly divided into normal control group, sham group and model group. The COPD rat models were developed by lipopolysaccharide (LPS). The changes of pulmonary function were detected at 28 d after modeling. The lung tissues of rats were observed by HE staining, and serum IFN-γ, IL-4, IL-12, and IL-13 were determined by ELISA. The mRNA expressions of IFN-γ and IL-4 were examined by PCR, and STAT4, STAT6 proteins in lung tissues were detected by Western blotting. Inflammation of lung tissues was more serious, the levels of serum IFN-γ, IL-12 and Th1/Th2, IFN-γ mRNA and STAT4 protein in lung tissues were higher, and lung function, the levels of serum IL-4 and IL-13, IL-4 mRNA and STAT6 protein in lung tissues were lower in model group than those in normal control and sham groups (P pulmonary function parameters and IFN-γ, Th1/Th2, STAT4 protein, and positive correlations between pulmonary function parameters and IL-4, IL-13, IL-4 mRNA, STAT6 protein (P < 0.01 or P < 0.05). The reduced lung function was found related to airway inflammation, cell Th1/Th2 imbalance in COPD. STAT4 and STAT6 involve in the regulation of Th1/Th2 cells. All of the above factors lead to the occurrence of COPD in rats.

  12. Changes of serum cytokines-related Th1/Th2/Th17 concentration in patients with postmenopausal osteoporosis.

    Science.gov (United States)

    Zhang, Jing; Fu, Qin; Ren, Zhaozhou; Wang, Yanjun; Wang, Chenchen; Shen, Tao; Wang, Guangbin; Wu, Lina

    2015-03-01

    Postmenopausal osteoporosis is now hypothetically considered to be an autoimmune and inflammatory process in which many pro-inflammatory and T cell-derived cytokines play important roles in the loss of bone mass. For instance, interleukin-2 (IL-2), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) secreted by Th1 and IL-6, IL-4, and IL-10 secreted by Th2 have been shown to be involved in the pathogenesis of osteoporosis. Interleukin-17 (IL-17) is a characteristic cytokine secreted by Th17 cells of the CD4 + subgroup. Although IL-17 has been shown to enhance bone resorption in ovariectomized mouse model, bone cells and genetic research, human-related studies of IL-17 are few. According to WHO classification of osteoporosis by the T scores of BMD, the subjects were divided into the postmenopausal osteoporosis group (T scores≤-2.5), the postmenopausal osteopenia group (-2.5 osteoporosis group than in the postmenopausal osteopenia group and the postmenopausal normal BMD group, but the difference between the postmenopausal osteopenia group and the postmenopausal normal BMD group had no statistical significance. IL-17A was negatively correlated with BMD. To our knowledge, we discovered for the first time that serum concentrations of IFN-γ and IL-4 were significantly lower in the postmenopausal osteoporosis group than in the postmenopausal normal BMD group; IFN-γ and IL-4 were positively correlated with BMD. In addition, we also determined that BMI was negatively correlated with BMD; IL-17A was positively correlated with serum calcium. However, no significant differences in IL-6, TNF-α, IL-2, and IL-10 were observed among the three groups; these three factors were not correlated with BMD. Our experiments have confirmed the roles of IL-17 in the pathogenesis of postmenopausal osteoporosis and in the promotion of bone resorption. Targeted therapy of IL-17, IFN-γ, and IL-4 may be beneficial in the treatment of patients with postmenopausal osteoporosis

  13. Highly dominating, highly authoritarian personalities.

    Science.gov (United States)

    Altemeyer, Bob

    2004-08-01

    The author considered the small part of the population whose members score highly on both the Social Dominance Orientation scale and the Right-Wing Authoritarianism scale. Studies of these High SDO-High RWAs, culled from samples of nearly 4000 Canadian university students and over 2600 of their parents and reported in the present article, reveal that these dominating authoritarians are among the most prejudiced persons in society. Furthermore, they seem to combine the worst elements of each kind of personality, being power-hungry, unsupportive of equality, manipulative, and amoral, as social dominators are in general, while also being religiously ethnocentric and dogmatic, as right-wing authoritarians tend to be. The author suggested that, although they are small in number, such persons can have considerable impact on society because they are well-positioned to become the leaders of prejudiced right-wing political movements.

  14. 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

    Full Text Available Abstract Background T lymphocytes are orchestrators of adaptive immunity. Naïve 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 performed comprehensive transcriptome analyses of Jurkat T cells stimulated with various stimuli and pathway inhibitors. Results from these experiments were validated in a human experimental setting using whole blood and purified CD4+ Tcells. Results Calcium-dependent activation of T cells using CD3/CD28 and PMA/CD3 stimulation induced a Th1 expression profile reflected by increased expression of T-bet, RUNX3, IL-2, and IFNγ, whereas calcium-independent activation via PMA/CD28 induced a Th2 expression profile which included GATA3, RXRA, CCL1 and Itk. Knock down with siRNA and gene expression profiling in the presence of selective kinase inhibitors showed that proximal kinases Lck and PKCθ are crucial signaling hubs during T helper cell activation, revealing a clear role for Lck in Th1 development and for PKCθ in both Th1 and Th2 development. Medial signaling via MAPkinases appeared to be less important in these pathways, since specific inhibitors of these kinases displayed a minor effect on gene expression. Translation towards a primary, whole blood setting and purified human CD4+ T cells revealed that PMA/CD3 stimulation induced a more pronounced Th1 specific, Lck and PKCθ dependent IFNγ production, whereas PMA/CD28 induced Th2 specific IL-5 and IL-13 production, independent of Lck activation. PMA/CD3-mediated skewing towards a Th1 phenotype was also reflected in mRNA expression of the master transcription factor Tbet, whereas PMA/CD28-mediated stimulation enhanced GATA3 mRNA expression in primary human CD4+ Tcells. Conclusions This study identifies stimulatory pathways and gene expression profiles for in vitro skewing of T helper cell

  15. Intranasal delivery of cholera toxin induces th17-dominated T-cell response to bystander antigens.

    Directory of Open Access Journals (Sweden)

    Jee-Boong Lee

    Full Text Available Cholera toxin (CT is a potent vaccine adjuvant, which promotes mucosal immunity to protein antigen given by nasal route. It has been suggested that CT promotes T helper type 2 (Th2 response and suppresses Th1 response. We here report the induction of Th17-dominated responses in mice by intranasal delivery of CT. This dramatic Th17-driving effect of CT, which was dependent on the B subunit, was observed even in Th1 or Th2-favored conditions of respiratory virus infection. These dominating Th17 responses resulted in the significant neutrophil accumulation in the lungs of mice given CT. Both in vitro and in vivo treatment of CT induced strongly augmented IL-6 production, and Th17-driving ability of CT was completely abolished in IL-6 knockout mice, indicating a role of this cytokine in the Th17-dominated T-cell responses by CT. These data demonstrate a novel Th17-driving activity of CT, and help understand the mechanisms of CT adjuvanticity to demarcate T helper responses.

  16. Visual dominance in olfactory memory.

    Science.gov (United States)

    Batic, N; Gabassi, P G

    1987-08-01

    The object of the present study was to verify the emergence of a 'visual dominance' effect in memory tests involving different sensory modes (sight and smell), brought about the preattentive mechanisms which select the visual sensory mode regardless of the recall task.

  17. Vector-meson dominance revisited

    Directory of Open Access Journals (Sweden)

    Terschlüsen Carla

    2012-12-01

    Full Text Available The interaction of mesons with electromagnetism is often well described by the concept of vector-meson dominance (VMD. However, there are also examples where VMD fails. A simple chiral Lagrangian for pions, rho and omega mesons is presented which can account for the respective agreement and disagreement between VMD and phenomenology in the sector of light mesons.

  18. Hand dominance in orthopaedic surgeons.

    LENUS (Irish Health Repository)

    Lui, Darren F

    2012-08-01

    Handedness is perhaps the most studied human asymmetry. Laterality is the preference shown for one side and it has been studied in many aspects of medicine. Studies have shown that some orthopaedic procedures had poorer outcomes and identified laterality as a contributing factor. We developed a questionnaire to assess laterality in orthopaedic surgery and compared this to an established scoring system. Sixty-two orthopaedic surgeons surveyed with the validated Waterloo Handedness Questionnaire (WHQ) were compared with the self developed Orthopaedic Handedness Questionnaire (OHQ). Fifty-eight were found to be right hand dominant (RHD) and 4 left hand dominant (LHD). In RHD surgeons, the average WHQ score was 44.9% and OHQ 15%. For LHD surgeons the WHQ score was 30.2% and OHQ 9.4%. This represents a significant amount of time using the non dominant hand but does not necessarily determine satisfactory or successful dexterity transferable to the operating room. Training may be required for the non dominant side.

  19. Testing for Stochastic Dominance Efficiency

    NARCIS (Netherlands)

    G.T. Post (Thierry); O. Linton; Y-J. Whang

    2005-01-01

    textabstractWe propose a new test of the stochastic dominance efficiency of a given portfolio over a class of portfolios. We establish its null and alternative asymptotic properties, and define a method for consistently estimating critical values. We present some numerical evidence that our

  20. 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

    by interleukin-4 (IL-4)-producing Th2 cells, or cure may result by Th1 cells secreting gamma interferon (IFN-gamma). The present study examined the potential of human T cells to generate Th1 or Th2 responses to L. donovani. The profiles of IFN-gamma, IL-4, and lymphotoxin secretion after antigen stimulation were...... analyzed in a panel of L. donovani-reactive CD4+ human T-cell clones generated from individuals who had recovered from VL after antimonial treatment. Two of the T-cell clones produced large amounts of IL-4 without production of IFN-gamma, seven clones produced both IFN-gamma and IL-4, and eight produced...

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

    International Nuclear Information System (INIS)

    Bass, H.; Adkins, B.; Strober, S.

    1991-01-01

    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

  2. Nanochip-induced Epithelial to Mesenchymal Transition: Impact of physical microenvironment on cancer metastasis.

    Science.gov (United States)

    Dhawan, Udesh; Sue, Ming-Wen; Chun Lan, Kuan; Buddhakosai, Waradee; Huang, Pao Hui; Chen, Yi Cheng; Chen, Po-Chun; Chen, Wen-Liang

    2018-03-20

    Epithelial to Mesenchymal transition (EMT) is a highly orchestrated process motivated by the nature of physical, chemical composition of Tumor Microenvironment (TME). The role of physical framework of the tumor microenvironment in guiding cells towards EMT is poorly understood. To investigate this, breast cancer MDA-MB-231 and MCF-7 cells were cultured on nanochips comprising of Tantalum oxide nanodots ranging in diameter from 10 to 200nm, fabricated through electrochemical approach and collectively referred to as artificial microenvironments. The 100 and 200nm nanochips induced cells to adopt an elongated or spindle shaped morphology. The key EMT genes, E-Cadherin, N-Cadherin and Vimentin, displayed the spatial control exhibited by the artificial microenvironments. The E-Cadherin gene expression was attenuated while of N-Cadherin and Vimentin was amplified by 100, 200nm nanochips indicating the induction of EMT. Transcription factors Snail, Twist were identified for modulating modulate EMT genes in the cells on these artificial microenvironments. Localization of EMT proteins observed through Immunostaining indicted the loss of cell-cell junctions on 100, 200nm nanochips, confirming the EMT induction. Thus, by utilizing an in-vitro approach, we demonstrate how the physical framework of TME may possibly trigger or assist in inducing EMT in-vivo. Applications in the fields of drug discovery, biomedical engineering and cancer research are expected.

  3. KEY FEATURES OF THE INTRAGRAFT MICROENVIRONMENT THAT DETERMINE LONG-TERM SURVIVAL FOLLOWING TRANSPLANTATION

    Directory of Open Access Journals (Sweden)

    Sarah eBruneau

    2012-04-01

    Full Text Available In this review, we discuss how changes in the intragraft microenvironment serve to promote or sustain the development of chronic allograft rejection. We propose two key elements within the microenvironment that contribute to the rejection process. The first is endothelial cell proliferation and angiogenesis that serve to create abnormal microvascular blood flow patterns as well as local tissue hypoxia, and precedes endothelial-to-mesenchymal transition (EndMT. The second is the overexpression of local cytokines and growth factors that serve to sustain inflammation and, in turn, function to promote a leukocyte-induced angiogenesis reaction. Central to both events is overexpression of vascular endothelial growth factor (VEGF, which is both pro-inflammatory and pro-angiogenic, and thus drives progression of the chronic rejection microenvironment. In our discussion, we focus on how inflammation results in angiogenesis and how leukocyte-induced angiogenesis is pathological. We also discuss how VEGF is a master control factor that fosters the development of the chronic rejection microenvironment. Overall, this review provides insight into the intragraft microenvironment as an important paradigm for future direction in the field.

  4. Assembly of hydrogel units for 3D microenvironment in a poly(dimethylsiloxane) channel

    Science.gov (United States)

    Cho, Chang Hyun; Kwon, Seyong; Park, Je-Kyun

    2017-12-01

    Construction of three-dimensional (3D) microenvironment become an important issue in recent biological studies due to their biological relevance compared to conventional two-dimensional (2D) microenvironment. Various fabrication techniques have been employed to construct a 3D microenvironment, however, it is difficult to fully satisfy the biological and mechanical properties required for the 3D cell culture system, such as heterogeneous tissue structures generated from the functional differences or diseases. We propose here an assembly method for facile construction of 3D microenvironment in a poly(dimethylsiloxane) (PDMS) channel using hydrogel units. The high-aspect-ratio of hydrogel units was achieved by fabricating these units using a 2D mold. With this approach, 3D heterogeneous hydrogel units were produced and assembled in a PDMS channel by structural hookup. In vivo-like 3D heterogeneous microenvironment in a precisely controllable fluidic system was also demonstrated using a controlled assembly of different types of hydrogel units, which was difficult to obtain from previous methods. By regulating the flow condition, the mechanical stability of the assembled hydrogel units was verified by the flow-induced deformation of hydrogel units. In addition, in vivo-like cell culture environment was demonstrated using an assembly of cell-coated hydrogel units in the fluidic channel. Based on these features, our method expects to provide a beneficial tool for the 3D cell culture module and biomimetic engineering.

  5. Activation of Pulmonary Dendritic Cells and Th2-Type Inflammatory Responses on Instillation of Engineered, Environmental Diesel Emission Source or Ambient Air Pollutant Particles in vivo

    Science.gov (United States)

    Bezemer, Gillina F.G.; Bauer, Stephen M.; Oberdörster, Günter; Breysse, Patrick N.; Pieters, Raymond H.H.; Georas, Steve N.; Williams, Marc A.

    2011-01-01

    The biological effects of acute particulate air pollution exposure in host innate immunity remain obscure and have relied largely on in vitro models. We hypothesized that single acute exposure to ambient or engineered particulate matter (PM) in the absence of other secondary stimuli would activate lung dendritic cells (DC) in vivo and provide information on the early immunological events of PM exposure and DC activation in a mouse model naïve to prior PM exposure. Activation of purified lung DC was studied following oropharyngeal instillation of ambient particulate matter (APM). We compared the effects of APM exposure with that of diesel-enriched PM (DEP), carbon black particles (CBP) and silver nanoparticles (AgP). We found that PM species induced variable cellular infiltration in the lungs and only APM exposure induced eosinophilic infiltration. Both APM and DEP activated pulmonary DC and promoted a Th2-type cytokine response from naïve CD4+ T cells ex vivo. Cultures of primary peribronchial lymph node cells from mice exposed to APM and DEP also displayed a Th2-type immune response ex vivo. We conclude that exposure of the lower airway to various PM species induces differential immunological responses and immunomodulation of DC subsets. Environmental APM and DEP activated DC in vivo and provoked a Th2 response ex vivo. By contrast, CBP and AgP induced altered lung tissue barrier integrity but failed to stimulate CD4+ T cells as effectively. Our work suggests that respirable pollutants activate the innate immune response with enhanced DC activation, pulmonary inflammation and Th2-immune responsiveness. PMID:21099199

  6. Increased hepatic Th2 and Treg subsets are associated with biliary fibrosis in different strains of mice caused by Clonorchis sinensis.

    Directory of Open Access Journals (Sweden)

    Bei-Bei Zhang

    Full Text Available Previous studies showed that CD4+T cells responses might be involved in the process of biliary fibrosis. However, the underlying mechanism resulting in biliary fibrosis caused by Clonorchis sinensis remains not yet fully elucidated. The objectives of the present study were to investigate the different profiles of hepatic CD4+T cell subsets (Th1, Th2, Th17 and Treg cells and their possible roles in the biliary fibrosis of different strains of mice (C57BL/6, BALB/c and FVB mice induced by C. sinensis infection. C57BL/6, BALB/c and FVB mice were orally gavaged with 45 metacercariae. All mice were sacrificed on 28 days post infection in deep anesthesia conditions. The leukocytes in the liver were separated to examine CD4+T cell subsets by flow cytometry and the left lobe of liver was used to observe pathological changes, collagen depositions and the concentrations of hydroxyproline. The most serious cystic and fibrotic changes appeared in FVB infected mice indicated by gross observation, Masson's trichrome staining and hydroxyproline content detection. In contrast to C57BL/6 infected mice, diffuse nodules and more intensive fibrosis were observed in the BALB/c infected mice. No differences of the hepatic Th1 subset and Th17 subset were found among the three strains, but the hepatic Th2 and Treg cells and their relative cytokines were dramatically increased in the BALB/c and FVB infected groups compared with the C57BL/6 infected group (P<0.01. Importantly, increased Th2 subset and Treg subset all positively correlated with hydroxyproline contents (P<0.01. This result for the first time implied that the increased hepatic Th2 and Treg cell subsets were likely to play potential roles in the formation of biliary fibrosis in C. sinensis-infected mice.

  7. 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.

  8. Mycophenolate Mofetil Modulates Differentiation of Th1/Th2 and the Secretion of Cytokines in an Active Crohn's Disease Mouse Model.

    Science.gov (United States)

    Lv, Qing-Kang; Liu, Ju-Xiong; Li, Su-Nan; Gao, Ying-Jie; Lv, Yan; Xu, Zi-Peng; Huang, Bing-Xu; Xu, Shi-Yao; Yang, Dong-Xue; Zeng, Ya-Long; Liu, Dian-Feng; Wang, Wei

    2015-11-06

    Mycophenolate mofetil (MMF) is an alternative immunosuppressive agent that has been reported to be effective and well tolerated for the treatment of refractory inflammatory bowel disease (IBD). The aim of this study was to investigate the therapeutic effect of MMF on intestinal injury and tissue inflammation, which were caused by Crohn's disease (CD). Here, trinitrobenzene sulfonic acid-relapsing (TNBS) colitis was induced in mice; then, we measured the differentiation of Th1/Th2 cells in mouse splenocytes by flow cytometry and the secretion of cytokines in mice with TNBS-induced colitis by real-time polymerase chain reaction and/or enzyme-linked immunosorbent assay (RT-PCR/ELISA). The results show that MMF significantly inhibited mRNA expression of pro-inflammatory cytokines IFN-γ, TNF-α, IL-12, IL-6, and IL-1β in mice with TNBS-induced colitis; however, MMF did not inhibit the expression of IL-10 mRNA. Additionally, ELISA showed that the serum levels of IFN-γ, TNF-α, IL-12, IL-6, and IL-1β were down-regulated in a TNBS model of colitis. Flow cytometric analysis showed MMF markedly reduced the percentages of Th1 and Th2 splenocytes in the CD mouse model. Mycophenolic acid (MPA) also significantly decreased the percentages of splenic Th1 and Th2 cells in vitro. Furthermore, MMF treatment not only significantly ameliorated diarrhea, and loss of body weight but also abrogated the histopathologic severity and inflammatory response of inflammatory colitis, and increased the survival rate of TNBS-induced colitic mice. These results suggest that treatment with MMF may improve experimental colitis and induce inflammatory response remission of CD by down-regulation of pro-inflammatory cytokines via modulation of the differentiation of Th1/Th2 cells.

  9. TNF-α inhibitors reduce the pathological Th1 -Th17 /Th2 imbalance in cutaneous mesenchymal stem cells of psoriasis patients.

    Science.gov (United States)

    Campanati, Anna; Orciani, Monia; Lazzarini, Raffaella; Ganzetti, Giulia; Consales, Veronica; Sorgentoni, Giulia; Di Primio, Roberto; Offidani, Annamaria

    2017-04-01

    Psoriasis is a disease characterized by an imbalance between Th 1 and Th 17 and Th 2 inflammatory axes, in which cutaneous mesenchymal stem cells (MSCs) are early involved, as they show a greater relative expression of several genes encoding for Th 1 and Th 17 cytokines. Therapeutic implications of TNF-α inhibitors on differentiated skin cells have been largely described in psoriasis; however, their effects on MSCs derived from patients with psoriasis have been only partially described. The aim of this work was to evaluate the effect of TNF-α inhibitors on cytokine milieu expressed by MSCs isolated from the skin of patients with psoriasis. Resident MSCs from skin of patients with psoriasis and healthy subjects have been isolated, characterized and profiled by PCR and ELISA for the expression of 22 cytokines involved in Th 1 , Th 2 and Th 17 pathways, both before and after 12 weeks therapy with TNF-α inhibitors. The administration of TNF-α inhibitors for 12-weeks acts on MSCs as follows: it reduces the expression of several Th 1 -Th 17 cytokines whose levels are elevated at baseline (IL-6, IL-8, IL-12, IL-23A, IFN-γ, TNF-α, CCL2, CCL20, CXCL2, CXCL5, IL-17A, IL-17C, IL-17F, IL-21, G-CSF). Similarly, it enhances the expression of several Th 2 cytokines which are underexpressed at baseline (IL-2, IL-4, IL-5), reducing the expression of those overexpressed at baseline (TGF-β and IL-13). TNF-α inhibitors could contribute to reduce the pathological imbalance between the Th 1 -Th 17 vs Th 2 axis in MSCs of patients with psoriasis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Gluten-free diet does not influence the occurrence and the Th1/Th17-Th2 nature of immune-mediated diseases in patients with coeliac disease.

    Science.gov (United States)

    Imperatore, Nicola; Rispo, Antonio; Capone, Pietro; Donetto, Sara; De Palma, Giovanni Domenico; Gerbino, Nicolò; Rea, Matilde; Caporaso, Nicola; Tortora, Raffaella

    2016-07-01

    Coeliac disease (CD) is the most common Th1-mediated enteropathy, frequently associated with other immune-mediated disorders (IMD). To evaluate: (1) the prevalence of IMD at the time of and after CD diagnosis; (2) a possible change in immune response to gluten free diet (GFD); (3) the potential role of GFD in reducing and/or preventing IMD in CD. Prospective study including all consecutive adult CD patients who underwent investigations for Th1-Th17/Th2-IMD at the time of CD diagnosis and after a 5-year follow-up period. 1255 CD were enrolled. Of these, 257 patients (20.5%) showed IMD at the time of CD diagnosis, with 58.4% presenting a Th1/Th17-IMD. After a 5-year follow-up period, 682 patients (54.3%) showed new IMD despite GFD. Of these, 57.3% presented a Th1/Th17-IMD and 42.7% a Th2-IMD (p=0.8). When compared the prevalence of each type of IMD before and after CD diagnosis, we did not identify any significant "switch" from Th1/Th17- to Th2-IMD or vice versa. The number of patients with Th1/Th17- and/or Th2-IMD increased during the GFD period (20.5% vs 54.3%; p<0.01; OR 1.9). The prevalence of IMD at the time of CD diagnosis is high and it seems to increase in the follow-up period despite GFD. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  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. Nickel, cobalt, chromium, palladium and gold induce a mixed Th1- and Th2-type cytokine response in vitro in subjects with contact allergy to the respective metals.

    Science.gov (United States)

    Minang, J T; Areström, I; Troye-Blomberg, M; Lundeberg, L; Ahlborg, N

    2006-12-01

    Nickel (Ni), the main cause of contact allergy to metals, induces in vitro production of both Th1- and Th2-type cytokines in peripheral blood mononuclear cells (PBMC) from allergic subjects. Because the knowledge of the cellular immune response to other metals involved in contact allergy has been limited, we investigated the cytokine profile induced by Ni, cobalt (Co), chromium (Cr), palladium (Pd) and gold (Au) in PBMC from patients with patch test reactivity to the respective metals. PBMC from patients with patch test reactivity to Ni, Co, Cr, Au and/or Pd (n = 31) and non-allergic controls (n = 5) were stimulated in vitro with corresponding metal salts. Th1- [interleukin (IL)-2 and interferon (IFN)-gamma] and Th2- (IL-4 and IL-13) type cytokine responses were measured by enzyme-linked immunospot (ELISpot) and/or enzyme-linked immunosorbent assay (ELISA). All metals induced a mixed Th1- and Th2-type cytokine production in PBMC from individual patients with patch test reactivity to the corresponding metal, but not in control PBMC. Significantly higher responses in the patient versus controls were found for Cr (IL-2 and IL-13), Pd (IL-2 and IL-4), Au (IL-13 and IFN-gamma) (all P < 0.05) and Ni (all four cytokines; P < 0.01) but not Co. Overall, 71% (37/52) and 89% (81/91) of the positive and negative patch test reactivities to metals, respectively, were matched by the in vitro reactivity. In conclusion, our data suggest that sensitization to Co, Cr, Pd and Au results in a cellular immune response of a character similar to the mixed Th1- and Th2-type cytokine profile shown previously to be induced by Ni.

  13. Locally instilled tumor necrosis factor α antisense oligonucleotide contributes to inhibition of TH 2-driven pulmonary fibrosis via induced CD4+ CD25+ Foxp3+ regulatory T cells.

    Science.gov (United States)

    Luo, Yi; Wang, Min; Pang, Zhonghua; Jiang, Fengtao; Chen, Jiangning; Zhang, Junfeng

    2013-01-01

    Anti-tumor necrosis factor α therapeutics has the potential to alleviate pulmonary fibrosis. However, the systemic administration of anti-tumor necrosis factor α agents has brought about contradictory results and frequent adverse effects, such as infections, immunogenicity and malignancies, amongst others. In the present study, we attempted the local administration of tumor necrosis factor α antisense oligonucleotide and evaluated the treatment effects on pulmonary fibrosis in a bleomycin-induced pulmonary fibrosis mouse model. Flow cytometry for regulatory T cells, reverse transcriptase-polymerase chain reaction for crucial gene expression, western blotting for crucial protein products, immunofluorescent analysis for T(H)2 cells and myofibroblasts, as well as histology analysis for pathological examination, were used. By local administration of tumor necrosis factor α antisense oligonucleotide, we investigated whether tumor necrosis factor α expression in epithelial cells was significantly inhibited and extracellular matrix overexpression was dramatically reduced. These treatment effects were associated with induced regulatory T cells, reduced T(H)2 cells and generally decreased T(H)2-type cytokine expression. Systemic immunosuppression was not triggered by local antisense oligonucleotide administration because the proportion of regulatory T cells in the blood, thymus or spleen was not affected. These findings demonstrate that local administration of tumor necrosis factor α antisense oligonucleotide contributes to anti-fibrotic action via a sustained up-regulated level of regulatory T cells, which inhibits T(H)2-biased responses, pro-fibrotic mediator production and extracellular matrix deposition, with no systemic immunosupression associated with systemically induced regulatory T cells. Copyright © 2013 John Wiley & Sons, Ltd.

  14. Sickness behavior induced by endotoxin can be mitigated by the dietary soluble fiber, pectin, through up-regulation of IL-4 and Th2 polarization

    OpenAIRE

    Sherry, Christina L.; Kim, Stephanie S.; Dilger, Ryan N.; Bauer, Laura L.; Moon, Morgan L.; Tapping, Richard I.; Fahey, George C.; Tappenden, Kelly A.; Freund, Gregory G.

    2010-01-01

    Peripheral activation of the immune system by infectious agents triggers the brain-cytokine system causing sickness behaviors which profoundly impact well-being. Dietary fiber is a beneficial foodstuff that, from a gastrointestinal tract perspective, exists in both insoluble and soluble forms. We show that a diet rich in soluble fiber protects mice from endotoxin-induced sickness behavior by polarizing mice Th2 when compared to a diet containing only insoluble fiber. Mice fed soluble fiber be...

  15. Testosterone-Mediated Endocrine Function and TH1/TH2 Cytokine Balance after Prenatal Exposure to Perfluorooctane Sulfonate: By Sex Status

    Directory of Open Access Journals (Sweden)

    Shou-Qiang Zhong

    2016-09-01

    Full Text Available Little information exists about the evaluation of potential developmental immunotoxicity induced by perfluorooctane sulfonate (PFOS, a synthetic persistent and increasingly ubiquitous environmental contaminant. To assess potential sex-specific impacts of PFOS on immunological health in the offspring, using male and female C57BL/6 mice, pups were evaluated for developmental immunotoxic effects after maternal oral exposure to PFOS (0.1, 1.0 and 5.0 mg PFOS/kg/day during Gestational Days 1–17. Spontaneous TH1/TH2-type cytokines, serum levels of testosterone and estradiol were evaluated in F1 pups at four and eight weeks of age. The study showed that male pups were more sensitive to the effects of PFOS than female pups. At eight weeks of age, an imbalance in TH1/TH2-type cytokines with excess TH2 cytokines (IL-4 was found only in male pups. As for hormone levels, PFOS treatment in utero significantly decreased serum testosterone levels and increased estradiol levels only in male pups, and a significant interaction between sex and PFOS was observed for serum testosterone at both four weeks of age (pinteraction = 0.0049 and eight weeks of age (pinteraction = 0.0227 and for estradiol alternation at four weeks of age (pinteraction = 0.0351. In conclusion, testosterone-mediated endocrine function may be partially involved in the TH1/TH2 imbalance induced by PFOS, and these deficits are detectable among both young and adult mice and may affect males more than females.

  16. Memory and flexibility of cytokine gene expression as separable properties of human T(H)1 and T(H)2 lymphocytes.

    Science.gov (United States)

    Messi, Mara; Giacchetto, Isabella; Nagata, Kinya; Lanzavecchia, Antonio; Natoli, Gioacchino; Sallusto, Federica

    2003-01-01

    CD4+ T cell priming under T helper type I (T(H)1) or T(H)2 conditions gives rise to polarized cytokine gene expression. We found that in these conditions human naive T cells acquired stable histone hyperacetylation at either the Ifng or Il4 promoter. Effector memory T cells showed polarized cytokine gene acetylation patterns in vivo, whereas central memory T cells had hypoacetylated cytokine genes but acquired polarized acetylation and expression after appropriate stimulation. However, hypoacetylation of the nonexpressed cytokine gene did not lead to irreversible silencing because most T(H)1 and T(H)2 cells acetylated and expressed the alternative gene when stimulated under opposite T(H) conditions. Such cytokine flexibility was absent in a subset of T(H)2 cells that failed to up-regulate T-bet and to express interferon-gamma when stimulated under T(H)1 conditions. Thus, most human CD4+ T cells retain both memory and flexibility of cytokine gene expression.

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

    Directory of Open Access Journals (Sweden)

    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.

  18. Overexpression of Notch ligand Delta-like-1 by dendritic cells enhances their immunoregulatory capacity and exerts antiallergic effects on Th2-mediated allergic asthma in mice.

    Science.gov (United States)

    Lee, Chen-Chen; Lin, Chu-Lun; Leu, Sy-Jye; Lee, Yueh-Lun

    2018-02-01

    Dendritic cells (DCs) are professional antigen-presenting cells, and Notch ligand Delta-like-1 (DLL1) on DCs was implicated in type 1T helper (Th1) differentiation. In this study, we produced genetically engineered bone marrow-derived DCs that expressed DLL1 (DLL1-DCs) by adenoviral transduction. DLL1-DCs exerted a fully mature phenotype, and had positive effects on expression levels of interleukin (IL)-12 and costimulatory molecules. Coculture of allogeneic T cells with ovalbumin (OVA)-pulsed DLL1-DCs enhanced T cell proliferative responses and promoted Th1 cell differentiation. Furthermore, adoptive transfer of OVA-stimulated DLL1-DCs into asthmatic mice alleviated the cardinal features of allergic asthma, including immunoglobulin E (IgE) production, airway hyperresponsiveness (AHR), airway inflammation, and production of Th2-type cytokines. Notably, enhanced levels of the Th1-biased IgG 2a response and interferon (IFN)-γ production were observed in these mice. Taken together, these data indicate that DLL1-DCs promoted Th1 cell development to alter the Th1/Th2 ratio and ameliorate Th2-mediated allergic asthma in mice. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    DEFF Research Database (Denmark)

    Blom, Lars; Poulsen, Lars K.

    2012-01-01

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

  20. 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 have...... impaired Th1 responses, whereas STAT6(-/-) mice do not generate normal Th2 responses. Cardiac allografts from C57BL/6 mice were transplanted into normal wild-type (WT), STAT4(-/-), and STAT6(-/-) BALB/c recipients. STAT4(-/-) and STAT6(-/-) mice rejected their grafts with the same tempo as untreated WT....... Furthermore, there was a similar differential effect of CD28-B7 versus CD154-CD40 blockade in inhibiting immune responses in animals immunized with ovalbumin and complete Freund's adjuvant. These novel data indicate that Th1 and Th2 cells are differentially regulated by CD28-B7 versus CD154-CD40 costimulation...

  1. Study on the correlationship between serum levels of sex hormones and Th1/Th2 cytokines in male patients with graves' disease

    International Nuclear Information System (INIS)

    Liu Li; Su Shengou; Zhang Xuekun; Wang Hongfen

    2009-01-01

    Objective: To explore the effect of sex hormones on the balance of Th1/Th2 in male patients with GD through investigation of changes of serum levels of sex hormones and cytokines (IFN-γ and IL-4) after treatment. Methods: Serum levels of E 2 , testosterone, FSH, LH (with RIA) and IFN-γ, IL-4 (with ELISA) were determined in 42 male patients with Graves' disease (both before and after 12 weeks of successful antithyroid therapy) and 40 controls. Results: The levels of E 2 , T, LH, FSH in the patients before treatment were significantly higher than those in the controls (P 2 was an independent fator affecting the levels of IL-4, and showed positive correlationship. The level of T was an independent factor affecting the levels of IFN-γ, also showed positive correlationship. The levels of IL-4 and IFN-γ were independent factors to each other, and there was negative correlationship between them. Conclusion: There were changes in levels of sex hormones and imbalance of Th1/Th2 in male patients with Graves' disease. The sex hormones might have some effect on Th1/Th2 balance in male patients with GD. (authors)

  2. 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.

  3. Rosae Multiflorae Fructus Hot Water Extract Inhibits a Murine Allergic Asthma Via the Suppression of Th2 Cytokine Production and Histamine Release from Mast Cells.

    Science.gov (United States)

    Song, Chang Ho; Bui, Thi Tho; Piao, Chun Hua; Shin, Hee Soon; Shon, Dong-Hwa; Han, Eui-Hyeog; Kim, Hyoung Tae; Chai, Ok Hee

    2016-09-01

    Mast cell-mediated anaphylactic reactions are involved in many allergic diseases, including asthma and allergic rhinitis. In Korea, where it has been used as a traditional medicine, Rosae Multiflorae fructus (RMF) is known to have potent antioxidative, analgesic, and anti-inflammatory activities and to have no obvious acute toxicity. However, its specific effect on asthma is still unknown. In this study, we evaluated whether or not RMF hot water extracts (RMFW) could inhibit ovalbumin (OVA)-induced allergic asthma and evaluated compound 48/80-induced mast cell activation to elucidate the mechanisms of asthma inhibition by RMFW. Oral administration of RMFW decreased the number of eosinophils and lymphocytes in the lungs of mice challenged by OVA and downregulated histological changes such as eosinophil infiltration, mucus accumulation, goblet cell hyperplasia, and collagen fiber deposits. In addition, RMFW significantly reduced T helper 2 cytokines, TNF-α, IL-4, and IL-6 levels in the BAL fluid of mice challenged by OVA. Moreover, RMFW suppressed compound 48/80-induced rat peritoneal mast cell degranulation and inhibited histamine release from mast cells induced by compound 48/80 in a dose-dependent manner. These results suggest that RMFW may act as an antiallergic agent by inhibitingTh2 cytokine production from Th2 cells and histamine release from mast cells, and could be used as a therapy for patients with Th2-mediated or mast cell-mediated allergic diseases.

  4. Non-invasive, epicutaneous immunisation with toxoid in deformable vesicles protects mice against tetanus, chiefly owing to a Th2 response.

    Science.gov (United States)

    Chopra, Amla; Cevc, Gregor

    2014-06-02

    A non-invasive, intra/transcutaneous immunisation of mice with a suitable combination of tetanus toxoid, ultradeformable vesicle (Transfersome®) carrier, and monophosphoryl lipid A adjuvant targets immuno-competent cells in a body and can protect 100% of the tested mice against an otherwise lethal (50×LD50) parenteral tetanus toxin challenge. The late immune response to the epicutaneously applied tetanus toxoid in such vesicles consists chiefly of circulating IgG1 and IgG2b antibody isotypes, indicative of a specific Th2 cellular response bias. Immunisations by subcutaneous injections moreover protect 100% of mice against a similar, otherwise lethal, dose of tetanus toxin. However, the immune response to transcutaneous and invasive immunisation differs. The latter elicits mainly IgG1 and IgG2b as well as IgG2a antibody isotypes, indicative of a mixed Th1/Th2 response. The cytokine response of the intra/transcutaneously and subcutaneously immunised mice reflects the difference in the organ-specific manner. IFN-γ concentration is appreciably increased in the draining lymph nodes and IL-10 in spleen. Since tetanus is a neutral antigen, both the Th1-specific IFN-γ and the Th-2 specific-IL-10 are observable. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Th1/M1 conversion to Th2/M2 responses in models of inflammation lacking cell death stimulates maturation of monocyte precursors to fibroblasts

    Directory of Open Access Journals (Sweden)

    JoAnn eTrial

    2013-09-01

    Full Text Available We have demonstrated that cardiac fibrosis arises from the differentiation of monocyte-derived fibroblasts. We present here evidence that this process requires sequential Th1 and Th2 induction promoting analogous M1 (classically activated and M2 (alternatively activated macrophage polarity. Our models are 1 mice subjected to daily repetitive ischemia reperfusion (I/R without infarction and 2 the in vitro transmigration of human mononuclear leukocytes through human cardiac microvascular endothelium. In the mouse heart, leukocytes entered after I/R in response to monocyte chemoattractant protein-1 (MCP-1 which is the major cytokine induced by this protocol. Monocytes within the heart then differentiated into fibroblasts making collagen while bearing the markers of M2 macrophages. T cells were seen in these hearts as well as in the human heart with cardiomyopathy. In the in vitro model, transmigration of the leukocytes was likewise induced by MCP-1 and some monocytes matured into fibroblasts bearing M2 markers. In this model, the MCP-1 stimulus induced a transient Th1 and M1 response that developed into a predominately Th2 and M2 response. An increase in the Th2 product IL-13 was present in both the human and the mouse models, consistent with its known role in fibrosis. In these simplified models, in which there is no cell death to stimulate an anti-inflammatory response, there is nonetheless a resolution of inflammation enabling a profibrotic environment. This induces the maturation of monocyte precursors into fibroblasts.

  6. Aberrant Production of Th1/Th2/Th17-Related Cytokines in Serum of C57BL/6 Mice after Short-Term Formaldehyde Exposure

    Directory of Open Access Journals (Sweden)

    Haiyan Wei

    2014-09-01

    Full Text Available Previous studies have shown that formaldehyde (FA could cause immunotoxicity by changing the number of T lymphocytes and that cytokines play a pivotal role in the regulation of T lymphocytes. However, the previously used cytokine detection methods are difficult to use in the measurement of several cytokines in a small amount of sample for one test. Therefore, the cytometric bead array (CBA technique was used. CBA showed better analytical efficiency and sensitivity than the previous methods. C57BL/6 mice were exposed to the control (normal saline, low FA concentration (0.5 mg/kg, and high FA concentration (2 mg/kg for 1 week or 1 month. The contents of cytokines, including Th1-related cytokines (IL-2, IFN-γ, and tumor necrosis factor, Th2-related cytokines (IL-4, IL-6, and IL-10, and Th17-related cytokines (IL-17A, were measured by using the BD FACS Canto II Flow Cytometer and analyzed by FCAP ArrayTM Software. Th1/Th2/Th17-related cytokines showed a slightly decreasing trend after low FA exposure. Conversely, a significantly increasing trend was found after high FA exposure. Th1/Th2/Th17-related cytokines all serve important functions in the immune reactions in mice after FA exposure.

  7. From nature-dominated to human-dominated environmental changes

    Science.gov (United States)

    Messerli, Bruno; Grosjean, Martin; Hofer, Thomas; Núñez, Lautaro; Pfister, Christian

    2000-01-01

    To what extent is it realistic and useful to view human history as a sequence of changes from highly vulnerable societies of hunters and gatherers through periods with less vulnerable, well buffered and highly productive agrarian-urban societies to a world with regions of extreme overpopulation and overuse of life support systems, so that vulnerability to climatic-environmental changes and extreme events is again increasing? This question cannot be fully answered in our present state of knowledge, but at least we can try to illustrate, with three case studies from different continents, time periods and ecosystems, some fundamental changes in the relationship between natural processes and human activities that occur, as we pass from a nature-dominated to a human dominated environment. 1. Early-mid Holocene: Nature dominated environment — human adaptation, mitigation, and migration. In the central Andes, the Holocene climate changed from humid (10,800-8000 BP) to extreme arid (8000-3600 BP) conditions. Over the same period, prehistoric hunting communities adopted a more sedentary pattern of resource use by settling close to the few perennial water bodies, where they began the process of domesticating camelids around 5000 BP and irrigation from about 3100 BP. 2. Historical period: An agrarian society in transition from an "enduring" to an innovative human response. Detailed documentary evidence from Western Europe may be used to reconstruct quite precisely the impacts of climatic variations on agrarian societies. The period considered spans a major transition from an apparently passive response to the vagaries of the environment during the 16th century to an active and innovative attitude from the onset of the agrarian revolution in the late 18th century through to the present day. The associated changes in technology and in agricultural practices helped to create a society better able to survive the impact of climatic extremes. 3. The present day: A human dominated

  8. Connected domination stable graphs upon edge addition ...

    African Journals Online (AJOL)

    A set S of vertices in a graph G is a connected dominating set of G if S dominates G and the subgraph induced by S is connected. We study the graphs for which adding any edge does not change the connected domination number. Keywords: Connected domination, connected domination stable, edge addition ...

  9. On dominator colorings in graphs

    Indian Academy of Sciences (India)

    Graph coloring and domination are two major areas in graph theory that have been ... independent set if no two vertices in S are adjacent. ... independent set. The corona G1 ◦ G2 of two graphs G1 and G2 is defined to be the graph. G obtained by taking one copy of G1 and |V(G1)| copies of G2, and then joining the i-th.

  10. Untangling Partnership and Domination Morality

    Directory of Open Access Journals (Sweden)

    David Loye

    2015-06-01

    Full Text Available Riane Eisler’s (1987 cultural transformation theory is an effective framework for understanding many of the constructs that shape society. This article uses Eisler’s theory to explain the formation of morality and the construction of conscience. It contrasts partnership morality and domination morality, and describes the factors that shape our tendency to embrace one or the other. The article helps us understand that we have a choice, and invites us to choose partnership morality.

  11. Perfis linfocitários Th1/Th2 e patogenia da co-infecção tuberculose/SIDA

    Directory of Open Access Journals (Sweden)

    M.A.T. Marques

    1999-09-01

    Full Text Available RESUMO: Em estudos anteriores, pudemos constatar que nos individuos VIH negactivos a gravidade da tuberculose pulmonar (TP era modulada pelos perfis linfodcários Th1/Th2 nas áreas lesadas: predomínio de Th1 (30.9±14.3/24.3±9.7% – p<0.04 e γ-INF (21.2.±3.4/7.3±1.8% – p<0.0002 e menores níveis de IL-4 (5.4±1.7/10.3±1.3% – p<0.0004 no LLBA das formas ligeiras, em relação às mais graves. No saogue, curiosamente, existia sempre um perfil Th1 superior ao Th2, independentemente da gravidade da situação. Neste contexto, procurouse averiguar as caraderísticas deste perfill no pulmão profundo de doentes co-infectados (SIDA/TP.Para isso estudou-se urn grupo de 16 individuos (13 homens e 3 mulberes, com uma média de idades de 39.4±10.8 anos, todos infectados pelo VIH1, sendo 9 deles toxirodependeotes através dos seguintes parâmetros: (1 determinação da celuldaridade total e percentual do LLBA em câmara de Neubauer e leitura por microscopia óptica; (2 contagem das populações (B e T e das subpopulações linfocitárias (CD4, CDB, γδ, CD16 CD56 e CD3+αβ-γδ; (3 avaliação do fenótipo Th1/Th2, através da contagem das células CD4+-CD7+(Th1 e CD4+CD7-(Th2. Estas dererminações, efeduadas no LLBA e sangue, foram obtidas com anticorpos monoclonais e leitura em citometria de fluxo.Dos resultados salientase: (1 presençã de uma ligeira alveolite (225±83.4 células/ml com predomíoio de macrófagos (92.4±3.5%; (2 importante queda da subpopulação CD4, tanto no LLBA (13.5±13% como no saogue (13.6±12%, acompanbada por uma expressiva elevação das células CD8 no LLBA (61.8±18%; (3 diminuição da actividade NK marcada pelos CD16 CD56 (2.2±1.1.6% no LLBA e 5.1±6.1% no sangue; (4 elevação do número de células duplamente negativas (7.9%±5.8% no LLBA e 6.4±4.3% no sangue

  12. [Bone and Stem Cells. Cellular network in bone micro-environment - histological and ultrastructural aspects -].

    Science.gov (United States)

    Amizuka, Norio; Yamamoto, Tomomaya; Hasegawa, Tomoka

    2014-04-01

    Bone micro-environment appears to reflect bone turnover, i.e., frequency of bone remodeling. There are many bone-synthesizing mature osteoblasts, bone-resorbing osteoclasts, and a thick cell layer of preosteoblasts overlying mature osteoblasts in the region which shows active bone remodeling. Bone lining cells, - flattened, resting form of osteoblasts cover the quiescent bone surface, in which, however, osteocyte-lacunar canalicular system tend to be geometrically well-arranged. Thus, bone micro-environment seems to be regulated by preosteoblasts, bone marrow stromal cells and vascular endothelial cells, as well as osteoblasts and osteoclasts. But, precious biological function of preosteoblasts and bone marrow stromal cells are still under the investigation, e.g., due to many phenotypes of preosteoblasts. In this review, we will introduce histological and ultrastructural aspects on cellular involvement in bone micro-environment.

  13. Breast cancer by proxy: Can the microenvironment be both the cause and consequence?

    Energy Technology Data Exchange (ETDEWEB)

    Ronnov-Jessen, Lone; Bissell, Mina J

    2008-11-16

    Breast cancer is one of the most clear-cut examples of a solid tumor in which systemic cues play a decisive part in its development. The breast tissue is constantly subjected to changes in hormone levels and modifications in the microenvironment. This scenario is even more striking during tumor development because of the dramatic loss or aberration of basement membrane (BM) and myoepithelial cells and the gain of peritumoral myofibroblasts. We suggest that the microenvironment, defined here as all components of the mammary gland other than luminal and/or tumor epithelial cells, might be instrumental in maintaining organ integrity and in promoting, and at times even initiating, breast cancer development. As such, the tumor microenvironment and its constituents, alone or in combination, might serve as promising targets for therapy.

  14. [Design of an anesthesia and micro-environment information management system in mobile operating room].

    Science.gov (United States)

    Wang, Xianwen; Liu, Zhiguo; Zhang, Wenchang; Wu, Qingfu; Tan, Shulin

    2013-08-01

    We have designed a mobile operating room information management system. The system is composed of a client and a server. A client, consisting of a PC, medical equipments, PLC and sensors, provides the acquisition and processing of anesthesia and micro-environment data. A server is a powerful computer that stores the data of the system. The client gathers the medical device data by using the C/S mode, and analyzes the obtained HL7 messages through the class library call. The client collects the micro-environment information with PLC, and finishes the data reading with the OPC technology. Experiment results showed that the designed system could manage the patient anesthesia and micro-environment information well, and improve the efficiency of the doctors' works and the digital level of the mobile operating room.

  15. [Advances in the effects of pH value of micro-environment on wound healing].

    Science.gov (United States)

    Tian, Ruirui; Li, Na; Wei, Li

    2016-04-01

    Wound healing is a complex regeneration process, which is affected by lots of endogenous and exogenous factors. Researches have confirmed that acid environment could prevent wound infection and accelerate wound healing by inhibiting bacteria proliferation, promoting oxygen release, affecting keratinocyte proliferation and migration, etc. In this article, we review the literature to identify the potential relationship between the pH value of wound micro-environment and the progress of wound healing, and summarize the clinical application of variation of pH value of micro-environment in wound healing, thereby to provide new treatment strategy for wound healing.

  16. The Colorectal Cancer Microenvironment: Strategies for Studying the Role of Cancer-Associated Fibroblasts.

    Science.gov (United States)

    Bhome, Rahul; Mellone, Massimiliano; Emo, Katherine; Thomas, Gareth J; Sayan, A Emre; Mirnezami, Alex H

    2018-01-01

    Colorectal cancer (CRC) is a key public health concern and the second highest cause of cancer related death in Western society. A dynamic interaction exists between CRC cells and the surrounding tumor microenvironment, which can stimulate not only the development of CRC, but its progression and metastasis, as well as the development of resistance to therapy. In this chapter, we focus on the role of fibroblasts within the CRC tumor microenvironment and describe some of the key methods for their study, as well as the evaluation of dynamic interactions within this biological ecosystem.

  17. Dominant Maneuver: The Art of the Possible

    National Research Council Canada - National Science Library

    Brozenick, Norman

    1997-01-01

    ...) dominant maneuver, (2) precision engagement, (3) full dimensional protection, and (4) focused logistics. This paper defines dominant maneuver as American maneuver warfare for the early 21st century...

  18. Organophosphate flame retardants (OPFRs) in indoor and outdoor air in the Rhine/Main area, Germany: comparison of concentrations and distribution profiles in different microenvironments.

    Science.gov (United States)

    Zhou, Lingli; Hiltscher, Marco; Gruber, Daniel; Püttmann, Wilhelm

    2017-04-01

    The concentrations of 9 organophosphate flame retardants (OPFRs) were determined in 56 indoor and 9 outdoor air samples in the Rhine/Main area in Germany. The indoor samples were collected from seven different indoor microenvironments including private cars, private homes, floor/carpet stores, building material markets, schools, offices, and day care centers, while outdoor samples were simultaneously collected close to the indoor sampling locations. The total OPFR concentrations (∑OPFRs) in indoor air ranged from 3.30 to 751.0 ng/m 3 with a median of 40.23 ng/m 3 , which was approximately eight times higher than those in outdoor air (median 5.38 ng/m 3 ), indicating that sources of OPFRs predominate in the indoor environment. Tris(2-chloroisopropyl)phosphate (TCPP), tris(isobutyl)phosphate (TiBP), and tributyl phosphate (TnBP) were the dominating compounds both in indoor and outdoor air. The median concentration of ∑OPFRs in private cars (180.3 ng/m 3 ) was significantly higher than that in private homes (12.51 ng/m 3 ), schools (36.23 ng/m 3 ), day care centers (31.80 ng/m 3 ), and building material markets (31.17 ng/m 3 ) (p TDCPP, and TCPP, whose concentrations were closely associated with the distribution profiles and pollution characteristics of materials predominating in different indoor microenvironments.

  19. Ergodic averages via dominating processes

    DEFF Research Database (Denmark)

    Møller, Jesper; Mengersen, Kerrie

    2006-01-01

    We show how the mean of a monotone function (defined on a state space equipped with a partial ordering) can be estimated, using ergodic averages calculated from upper and lower dominating processes of a stationary irreducible Markov chain. In particular, we do not need to simulate the stationary...... Markov chain and we eliminate the problem of whether an appropriate burn-in is determined or not. Moreover, when a central limit theorem applies, we show how confidence intervals for the mean can be estimated by bounding the asymptotic variance of the ergodic average based on the equilibrium chain....

  20. Adverse genomic alterations and stemness features are induced by field cancerization in the microenvironment of hepatocellular carcinomas

    DEFF Research Database (Denmark)

    Castven, Darko; Fischer, Michael; Becker, Diana

    2017-01-01

    .Prognostic significance of the permissive liver microenvironment might be a consequence of a pro-oncogenic field effect that is caused by chronic regenerative processes. Activation of key oncogenic features and immune-response signaling indicates that the cross-talk between tumor and microenvironment might be a promising...

  1. Fasciola hepatica reinfection potentiates a mixed Th1/Th2/Th17/Treg response and correlates with the clinical phenotypes of anemia

    Science.gov (United States)

    Perez-Crespo, Ignacio; Chillón-Marinas, Carlos; Khoubbane, Messaoud; Quesada, Carla; Reguera-Gomez, Marta; Mas-Coma, Santiago; Fresno, Manuel; Gironès, Núria

    2017-01-01

    Background Fascioliasis is a severe zoonotic disease of worldwide extension caused by liver flukes. In human fascioliasis hyperendemic areas, reinfection and chronicity are the norm and anemia is the main sign. Herein, the profile of the Th1/Th2/Th17/Treg expression levels is analyzed after reinfection, correlating them with their corresponding hematological biomarkers of morbidity. Methodology/Principal findings The experimental design reproduces the usual reinfection/chronicity conditions in human fascioliasis endemic areas and included Fasciola hepatica primo-infected Wistar rats (PI) and rats reinfected at 8 weeks (R8), and at 12 weeks (R12), and negative control rats. In a cross-sectional study, the expression of the genes associated with Th1 (Ifng, Il12a, Il12b, Nos2), Th2 (Il4, Arg1), Treg (Foxp3, Il10, Tgfb, Ebi3), and Th17 (Il17) in the spleen and thymus was analyzed. After 20 weeks of primary infection, PI did not present significant changes in the expression of those genes when compared to non-infected rats (NI), but an increase of Il4, Arg1 and Ifng mRNA in the spleen was observed in R12, suggesting the existence of an active mixed Th1/Th2 systemic immune response in reinfection. Foxp3, Il10, Tgfb and Ebi3 levels increased in the spleen in R12 when compared to NI and PI, indicating that the Treg gene expression levels are potentiated in chronic phase reinfection. Il17 gene expression levels in R12 in the spleen increased when compared to NI, PI and R8. Gene expression levels of Il10 in the thymus increased when compared to NI and PI in R12. Ifng expression levels in the thymus increased in all reinfected rats, but not in PI. The clinical phenotype was determined by the fluke burden, the rat body weight and the hemogram. Multivariate mathematical models were built to describe the Th1/Th2/Th17/Treg expression levels and the clinical phenotype. In reinfection, two phenotypic patterns were detected: i) one which includes only increased splenic Ifng

  2. Fasciola hepatica reinfection potentiates a mixed Th1/Th2/Th17/Treg response and correlates with the clinical phenotypes of anemia.

    Science.gov (United States)

    Valero, M Adela; Perez-Crespo, Ignacio; Chillón-Marinas, Carlos; Khoubbane, Messaoud; Quesada, Carla; Reguera-Gomez, Marta; Mas-Coma, Santiago; Fresno, Manuel; Gironès, Núria

    2017-01-01

    Fascioliasis is a severe zoonotic disease of worldwide extension caused by liver flukes. In human fascioliasis hyperendemic areas, reinfection and chronicity are the norm and anemia is the main sign. Herein, the profile of the Th1/Th2/Th17/Treg expression levels is analyzed after reinfection, correlating them with their corresponding hematological biomarkers of morbidity. The experimental design reproduces the usual reinfection/chronicity conditions in human fascioliasis endemic areas and included Fasciola hepatica primo-infected Wistar rats (PI) and rats reinfected at 8 weeks (R8), and at 12 weeks (R12), and negative control rats. In a cross-sectional study, the expression of the genes associated with Th1 (Ifng, Il12a, Il12b, Nos2), Th2 (Il4, Arg1), Treg (Foxp3, Il10, Tgfb, Ebi3), and Th17 (Il17) in the spleen and thymus was analyzed. After 20 weeks of primary infection, PI did not present significant changes in the expression of those genes when compared to non-infected rats (NI), but an increase of Il4, Arg1 and Ifng mRNA in the spleen was observed in R12, suggesting the existence of an active mixed Th1/Th2 systemic immune response in reinfection. Foxp3, Il10, Tgfb and Ebi3 levels increased in the spleen in R12 when compared to NI and PI, indicating that the Treg gene expression levels are potentiated in chronic phase reinfection. Il17 gene expression levels in R12 in the spleen increased when compared to NI, PI and R8. Gene expression levels of Il10 in the thymus increased when compared to NI and PI in R12. Ifng expression levels in the thymus increased in all reinfected rats, but not in PI. The clinical phenotype was determined by the fluke burden, the rat body weight and the hemogram. Multivariate mathematical models were built to describe the Th1/Th2/Th17/Treg expression levels and the clinical phenotype. In reinfection, two phenotypic patterns were detected: i) one which includes only increased splenic Ifng expression levels but no Treg expression

  3. Improvement in Th1/Th2 immune homeostasis, antioxidative status and resistance to pathogenic E. coli on consumption of probiotic Lactobacillus rhamnosus fermented milk in aging mice.

    Science.gov (United States)

    Sharma, Rohit; Kapila, Rajeev; Dass, Gulshan; Kapila, Suman

    2014-01-01

    Imbalance in Th1/Th2 immune pathways and cellular antioxidant systems with progressive aging are among the leading causes of increased risk of morbidity and mortality in elderly. Although probiotics have been considered to boost immune system, there is a lack of comprehensive analysis of probiotic effects on aging physiology. The present study aimed at determining anti-immunosenescence potential of milk fermented with probiotic Lactobacillus rhamnosus (LR) in 16 months old mice by concurrent analysis of immunosenescence markers associated with Th1/Th2 profile of splenocytes, inflamm-aging in plasma, neutrophil functions and antibody response in intestine along with analysis of antioxidant enzymes in liver and red blood cells (RBCs) after feeding trials of 1 and 2 months, respectively. An enteropathogenic Escherichia coli (ATCC 14948)-based infection model in aging mice was also designed to validate protective attributes of LR. Splenocytes registered increased IFN-γ and decreased IL-4 and IL-10 production in LR-fed animals. Neutrophil respiratory burst enzymes and phagocytosis increased significantly while no aggravation in plasma levels of MCP-1 and TNF-α was observed. Further, owing to increased Th1 response, antibodies registered a decrease in IgG1/IgG2a ratio and IgE levels in LR groups. No significant variations were observed in secretory IgA and IgA + cells in the intestine. Antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) in LR-fed groups recorded increased activities which were more pronounced in the liver than in RBCs. LR supplementation significantly reduced E. coli translocation to organs (intestine, liver, spleen, peritoneal fluid) by enhancing E. coli-specific antibodies (IgA and IgG1) and inflammatory proteins. In conclusion, LR supplementation alleviated immunosenescence-associated Th1/Th2 imbalance, improved antioxidant capacity, and enhanced resistance of aged mice to E. coli infection thereby signifying its potential

  4. Chemokine Receptor Expression Identifies Pre–T Helper (Th)1, Pre–Th2, and Nonpolarized Cells among Human CD4+ Central Memory T Cells

    Science.gov (United States)

    Rivino, Laura; Messi, Mara; Jarrossay, David; Lanzavecchia, Antonio; Sallusto, Federica; Geginat, Jens

    2004-01-01

    We previously reported that central–memory T cells (TCM cells), which express lymph node homing receptors CCR7 and CD62L, are largely devoid of effector functions but acquire characteristics of effector–memory T cells (TEM cells) (i.e., CCR7− T helper [Th]1 or Th2 cells) after stimulation with T cell receptor agonists or homeostatic cytokines. Here we show that three chemokine receptors identify functional subsets within the human CD4+ TCM cell pool. TCM cells expressing CXCR3 secreted low amounts of interferon γ, whereas CCR4+ TCM cells produced some interleukin (IL)-4, but not IL-5. In response to IL-7 and IL-15, CXCR3+ TCM and CCR4+ TCM cells invariably generated fully differentiated CCR7− Th1 and Th2 cells, respectively, suggesting that they represent pre-Th1 and pre-Th2 cells. Conversely, CXCR5+ TCM cells lacking CXCR3 and CCR4 remained nonpolarized and retained CCR7 and CD62L expression upon cytokine-driven expansion. Unlike naive cells, all memory subsets had a low T cell receptor rearrangement excision circle content, spontaneously incorporated bromodeoxyuridine ex vivo, and contained cells specific for tetanus toxoid. Conversely, recall responses to cytomegalovirus and vaccinia virus were largely restricted to CXCR3+ TCM and TEM cells. We conclude that antigen-specific memory T cells are distributed between TEM cells and different subsets of TCM cells. Our results also explain how the quality of primary T cell responses could be maintained by TCM cells in the absence of antigen. PMID:15381728

  5. Curcumin attenuates the scurfy-induced immune disorder, a model of IPEX syndrome, with inhibiting Th1/Th2/Th17 responses in mice.

    Science.gov (United States)

    Lee, Gihyun; Chung, Hwan-Suck; Lee, Kyeseok; Lee, Hyeonhoon; Kim, Minhwan; Bae, Hyunsu

    2017-09-15

    Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) is a lethal autoimmune disease caused by mutations in the Foxp3 gene scurfin (scurfy). Immunosuppressive therapy for IPEX patients has been generally ineffective and has caused severe side effects, however curcumin has shown immune regulation properties for inflammatory diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel diseases without side effects. The aim of this study was to investigate whether curcumin would attenuate symptoms of IPEX in mouse model and would prolong its survival period. C57BL/6 mice were separated into scurfy or wild-type litter mate groups by genotyping, and each group subsequently was separated into 2 subgroups that were fed a 1% curcumin containing or normal diet from the last day of breast-feeding. After weaning, pups were fed either a 1% curcumin containing or normal diet until all scurfy mice die for survival data. To elucidate immune cell proportions in spleen and lymph nodes, cells were analyzed by flowcytometry. Cellular cytokine production was accessed to investigate the effects of curcumin in T cell differentiation in vitro. Scurfy mice fed a 1% curcumin diet survived 4.0-fold longer compared to scurfy (92.5 days) mice fed a normal diet (23 days). A curcumin diet decreased all of the Th1/Th2/Th17 cell populations and attenuated diverse symptoms such as splenomegaly in scurfy mice. In vitro experiments showed that curcumin treatment directly decreased the Th1/Th2/Th17 cytokine production of IFN-γ, IL-4, and IL-17A in CD4 + T cells. Curcumin diet attenuated the scurfy-induced immune disorder, a model of IPEX syndrome, by inhibiting Th1/Th2/Th17 responses in mice. These results have implications for improving clinical therapy for patients with IPEX and other T cell related autoimmune diseases. Copyright © 2017 Elsevier GmbH. All rights reserved.

  6. CD4+ Th17 cells discriminate clinical types and constitute a third subset of non Th1, Non Th2 T cells in human leprosy.

    Directory of Open Access Journals (Sweden)

    Chaman Saini

    Full Text Available BACKGROUND: Patients with localized tuberculoid and generalized lepromatous leprosy show respectively Th1 and Th2 cytokine profile. Additionally, other patients in both types of leprosy also show a non discriminating Th0 cytokine profile with both interferon-γ and IL-4. The present study investigated the role of Th17 cells which appear to be a distinct subtype of Th subtypes in 19 tuberculoid and 18 lepromatous leprosy patients. Five healthy subjects with long term exposure to infection and 4 skin biopsies from healthy subjects undergoing cosmetic surgery were used as controls. METHODOLOGY/PRINCIPLE FINDINGS: An array of Th17 related primers for cytokines, chemokines and transcription factors was used in real time reverse transcribed PCR to evaluate gene expression, ELISA for cytokine secretion in the supernatants of antigen stimulated PBMC cultures and flow cytometry for establishing the phenotype of the IL-17, IL-21 producing cells. CONCLUSIONS/SIGNIFICANCE: IL-17 isoforms showed significantly higher expression and release in supernatants of antigen stimulated PBMC cultures and dermal lesions of healthy contacts and tuberculoid leprosy as compared to lepromatous leprosy (p<0.003. This was further confirmed by Th17 associated transcription factor RORC, cytokines IL-21, IL-22, and IL-23, chemokines MMP13, CCL20, CCL22. Of interest was the association of IL-23R and not IL-6R with IL-17(+ cells. The Th17 cells were CD4(+ CCR6(+ confirming their effector cell lineage. Polarized Th1 cytokines were seen in 3/7 tuberculoid and Th2 cytokines in 5/10 lepromatous leprosy patients. Of importance was the higher association of Th17 pathway factors with the non-polarized Th0 types as compared to the polarized Th1 and Th2 (p<0.01. Our study draws attention to a third type of effector Th cell that may play a role in leprosy.

  7. Ferulic acid supresses Th2 immune response and prevents remodeling in ovalbumin-induced pulmonary allergy associated with inhibition of epithelial-derived cytokines.

    Science.gov (United States)

    Sin Singer Brugiolo, Alessa; Carvalho Gouveia, Ana Cláudia; de Souza Alves, Caio César; de Castro E Silva, Flávia Márcia; Esteves de Oliveira, Érick; Ferreira, Ana Paula

    2017-08-01

    Asthma is characterized by intermittent airway obstruction and chronic inflammation, orchestrated primarily by Th2 cytokines. There is a strong rationale for developing new asthma therapies, since current treatment protocols present side effects and may not be effective in cases of difficult-to-control asthma. The purpose of this study was to evaluate the effect of ferulic acid, a phenolic acid commonly present in plants, in the ovalbumin-induced pulmonary allergy murine model. BALB/c mice were sensitized and challenged with ovalbumin, and treatments were provided by gavage. Six groups of mice (n = 6) were studied, labeled as: control, pulmonary allergy, dexamethasone, and 3 receiving ferulic acid (at 25, 50, and 100 mg/kg). Lung tissue, bronchoalveolar lavage fluid and serum were collected for analysis. Ferulic acid treatment inhibited an established allergic Th2-response by decreasing the key features of pulmonary allergy, including lung and airway inflammation, eosinophil infiltration, mucus production and serum levels of OVA-specific IgE. These results were associated with lower levels of CCL20, CCL11 and CCL5 chemokines and IL-4, IL-5, IL-13, TSLP, IL-25 and IL-33 cytokines in lung tissue homogenate. In this study it was demonstrated for the first time that ferulic acid treatment is able to suppress one of the main features of the airway remodeling, indicated by reduction of mucus production, besides the Th2 pathogenic response on ovalbumin-induced pulmonary allergy. Taken together, results shows that the immunopathological mechanism underlying these effects is linked to a reduction of the epithelial-derived chemokines and cytokines, suggesting that ferulic acid may be useful as a potential therapeutic agent for asthma. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Nickel elicits concomitant and correlated in vitro production of Th1-, Th2-type and regulatory cytokines in subjects with contact allergy to nickel.

    Science.gov (United States)

    Minang, J T; Troye-Blomberg, M; Lundeberg, L; Ahlborg, N

    2005-09-01

    Nickel (Ni2+) elicits production of functionally distinct cytokines in vitro, but the relation between the cytokine profile and the degree of the allergic reaction in vivo needs to be better defined in order to improve the understanding of the immunological mechanisms involved in contact allergy and to facilitate development of in vitro diagnostics. The aim of the study was to define Th1-type [interferon-gamma (IFN-gamma)], Th2-type [interleukin-4 (IL-4), IL-5 and IL-13] and regulatory (IL-10) cytokine responses to Ni2+ in peripheral blood mononuclear cells (PBMC) from subjects with varying patch test reactivity to Ni2+. The study included subjects with strong (+3), moderate (+2), weak (+1) or negative (controls) patch test reactivity to Ni2+ (n = 10 per group). All +3 and +2 subjects but only three +1 subjects had a clinical history of contact allergy to Ni(2+). Cytokine production of PBMC stimulated with Ni(2+) was determined by enzyme-linked immunospot and/or enzyme-linked immunosorbent assay. Ni2+ elicited significant production of all cytokines in PBMC from patch-test-positive subjects versus controls with a positive correlation between each cytokine and the patch test reactivity as well as with other cytokines. More subjects responded to Ni2+ above cut-off values with Th2-type cytokines as compared with IFN-gamma or IL-10; 100% of +3, 80% of +2, 50% of +1 and 0% of control subjects displayed reactivity to Ni2+ based on IL-4 and IL-13 assays. Despite the prevailing view of Ni2+ allergy as a type-1-mediated condition, the in vivo reactivity to Ni2+ correlated with a mixed Th1-type, Th2-type and regulatory cytokine response to Ni2+in vitro. The results accentuate the importance of type 2 responses in contact allergy and also demonstrate that IL-4 and IL-13 are reliable markers for Ni2+ allergy.

  9. Role of NF-κB activation and Th1/Th2 imbalance in pulmonary toxicity induced by nano NiO.

    Science.gov (United States)

    Chang, Xuhong; Zhu, An; Liu, Fangfang; Zou, Lingyue; Su, Li; Li, Sheng; Sun, Yingbiao

    2017-04-01

    With the progress of nanotechnology, nano nickel oxide (NiO) has been extensively used as sensors, battery electrodes, catalysts, and cosmetics. Previous researches verified that nano NiO could exert pulmonary toxicity, but its mechanism was unclear. To shed light upon this, the role of nuclear factor-κB (NF-κB) activation and Th1/Th2 imbalance were to explore in pulmonary damage induced by nano NiO. Male Wistar rats were randomized into control group, nano NiO groups (0.015, 0.06, and 0.24 mg kg -1 ) and micro NiO group (0.024 mg kg -1 ) and treated by intratracheal instillation twice a week for 6 weeks. The results showed that the abnormal changes induced by nano NiO were found on indicators of nitrative stress (NO, TNOS, and iNOS), inflammatory cytokines (TNF-α, IL-2, and IL-10) and cytokine-induced neutrophil chemoattractants (CINC-1, CINC-2αβ, and CINC-3) in lung tissue. In addition, nano NiO instillation induced the upregulated mRNA and protein expression of NF-κB, inhibitor of κB kinase-α (IKK-α) and nuclear factor-inducing kinase (NIK). The protein content of GATA-3 increased as well as T-bet decreased in nano NiO groups, and the ratio of T-bet/GATA-3, as a key evaluation indicator of Th1/Th2 balance, was lower than the control group. The findings indicated that nano NiO could enhance the nitrative stress and inflammatory response in lung tissue, and its mechanism was related to the NF-κB activation and Th1/Th2 imbalance. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1354-1362, 2017. © 2016 Wiley Periodicals, Inc.

  10. Characterization of the subsets of human NKT-like cells and the expression of Th1/Th2 cytokines in patients with unexplained recurrent spontaneous abortion.

    Science.gov (United States)

    Yuan, Jing; Li, Jian; Huang, Shi-Yun; Sun, Xin

    2015-08-01

    The objective was to investigate the subsets of natural killer T (NKT)-like cells and the expression of Th1/Th2 cytokines in the peripheral blood (PB) and/or decidual tissue of patients with unexplained recurrent spontaneous abortion (URSA). The percentages of NKT-like cells in the PB and deciduas of URSA patients in early pregnancy and in the PB of nonpregnant women were analyzed by flow cytometry. The expression of interferon (IFN)-γ (Th1 cytokine) and Th2 cytokines, interleukin (IL)-4 and IL-10, in the PB and decidual tissue was measured by quantitative RT-PCR and enzyme-linked immunosorbent assay (ELISA). Most percentages of subsets of NKT-like cells (CD3(+)CD56(+), CD3(+)CD56(+)CD16(+)) in the PB and deciduas were significantly greater in URSA patients than in normal pregnant and nonpregnant women. A cut-off value of 3.75% for the increased percentage of CD3(+)CD56(+)CD16(+) NKT-like cells in the PB appeared to be predictive of pregnancy failure. Moreover, we found that in the decidua, IFN-γ expression was significantly higher, while IL-4 and IL-10 expression was significantly lower in URSA patients compared with those with a normal pregnancy. The ratio of decidual Th1/Th2 cytokines in URSA patients was significantly increased compared with that in normal pregnant women. Decidual IL-4 expression correlated negatively with the percentages of blood CD3(+)CD56(+)CD16(+) NKT-like cells and the decidual CD3(+)CD56(+) and CD3(+)CD56(+)CD16(+) NKT-like cells. NKT-like cells may play an important role in maintaining normal pregnancy. Measurement of CD3(+)CD56(+)CD16(+) NKT-like cells in the PB may provide a potential tool for assessing patients' risk of spontaneous abortion. Copyright © 2015. Published by Elsevier Ireland Ltd.

  11. 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.

  12. Breast cancer by proxy: can the microenvironment be both the cause and consequence?

    DEFF Research Database (Denmark)

    Rønnov-Jessen, Lone; Bissell, Mina J

    2009-01-01

    Breast cancer is one of the most clear-cut examples of a solid tumor in which systemic cues play a decisive part in its development. The breast tissue is constantly subjected to changes in hormone levels and modifications in the microenvironment. This scenario is even more striking during tumor d...

  13. Carbonic anhydrase IX (CA IX) mediates tumor cell interactions with microenvironment

    Czech Academy of Sciences Publication Activity Database

    Závadová, Zuzana; Závada, Jan

    2005-01-01

    Roč. 13, č. 5 (2005), s. 977-982 ISSN 1021-335X R&D Projects: GA ČR(CZ) GA203/02/0405 Institutional research plan: CEZ:AV0Z50520514 Keywords : carbonic anhydrase IX * cell adhesion * microenvironment Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.572, year: 2005

  14. Immunotherapeutic Potential of Oncolytic H-1 Parvovirus: Hints of Glioblastoma Microenvironment Conversion towards Immunogenicity.

    Science.gov (United States)

    Angelova, Assia L; Barf, Milena; Geletneky, Karsten; Unterberg, Andreas; Rommelaere, Jean

    2017-12-15

    Glioblastoma, one of the most aggressive primary brain tumors, is characterized by highly immunosuppressive microenvironment. This contributes to glioblastoma resistance to standard treatment modalities and allows tumor growth and recurrence. Several immune-targeted approaches have been recently developed and are currently under preclinical and clinical investigation. Oncolytic viruses, including the autonomous protoparvovirus H-1 (H-1PV), show great promise as novel immunotherapeutic tools. In a first phase I/IIa clinical trial (ParvOryx01), H-1PV was safe and well tolerated when locally or systemically administered to recurrent glioblastoma patients. The virus was able to cross the blood-brain (tumor) barrier after intravenous infusion. Importantly, H-1PV treatment of glioblastoma patients was associated with immunogenic changes in the tumor microenvironment. Tumor infiltration with activated cytotoxic T cells, induction of cathepsin B and inducible nitric oxide (NO) synthase (iNOS) expression in tumor-associated microglia/macrophages (TAM), and accumulation of activated TAM in cluster of differentiation (CD) 40 ligand (CD40L)-positive glioblastoma regions was detected. These are the first-in-human observations of H-1PV capacity to switch the immunosuppressed tumor microenvironment towards immunogenicity. Based on this pilot study, we present a tentative model of H-1PV-mediated modulation of glioblastoma microenvironment and propose a combinatorial therapeutic approach taking advantage of H-1PV-induced microglia/macrophage activation for further (pre)clinical testing.

  15. Microscale screening systems for 3D cellular microenvironments: platforms, advances, and challenges.

    Science.gov (United States)

    Montanez-Sauri, Sara I; Beebe, David J; Sung, Kyung Eun

    2015-01-01

    The increasing interest in studying cells using more in vivo-like three-dimensional (3D) microenvironments has created a need for advanced 3D screening platforms with enhanced functionalities and increased throughput. 3D screening platforms that better mimic in vivo microenvironments with enhanced throughput would provide more in-depth understanding of the complexity and heterogeneity of microenvironments. The platforms would also better predict the toxicity and efficacy of potential drugs in physiologically relevant conditions. Traditional 3D culture models (e.g., spinner flasks, gyratory rotation devices, non-adhesive surfaces, polymers) were developed to create 3D multicellular structures. However, these traditional systems require large volumes of reagents and cells, and are not compatible with high-throughput screening (HTS) systems. Microscale technology offers the miniaturization of 3D cultures and allows efficient screening of various conditions. This review will discuss the development, most influential works, and current advantages and challenges of microscale culture systems for screening cells in 3D microenvironments.

  16. 3D bioprinting: improving in vitro models of metastasis with heterogeneous tumor microenvironments

    Science.gov (United States)

    Albritton, Jacob L.

    2017-01-01

    ABSTRACT Even with many advances in treatment over the past decades, cancer still remains a leading cause of death worldwide. Despite the recognized relationship between metastasis and increased mortality rate, surprisingly little is known about the exact mechanism of metastatic progression. Currently available in vitro models cannot replicate the three-dimensionality and heterogeneity of the tumor microenvironment sufficiently to recapitulate many of the known characteristics of tumors in vivo. Our understanding of metastatic progression would thus be boosted by the development of in vitro models that could more completely capture the salient features of cancer biology. Bioengineering groups have been working for over two decades to create in vitro microenvironments for application in regenerative medicine and tissue engineering. Over this time, advances in 3D printing technology and biomaterials research have jointly led to the creation of 3D bioprinting, which has improved our ability to develop in vitro models with complexity approaching that of the in vivo tumor microenvironment. In this Review, we give an overview of 3D bioprinting methods developed for tissue engineering, which can be directly applied to constructing in vitro models of heterogeneous tumor microenvironments. We discuss considerations and limitations associated with 3D printing and highlight how these advances could be harnessed to better model metastasis and potentially guide the development of anti-cancer strategies. PMID:28067628

  17. Human body micro-environment: The benefits of controlling airflow interaction

    DEFF Research Database (Denmark)

    Melikov, Arsen Krikor

    2015-01-01

    This paper focuses on the micro-environment around a human body, and especially on its interaction with the surrounding environment. Research on the free convection flow generated by a human body (including the convective boundary layer around the body and the thermal plume above the body), its...

  18. Human mammary microenvironment better regulates the biology of human breast cancer in humanized mouse model.

    Science.gov (United States)

    Zheng, Ming-Jie; Wang, Jue; Xu, Lu; Zha, Xiao-Ming; Zhao, Yi; Ling, Li-Jun; Wang, Shui

    2015-02-01

    During the past decades, many efforts have been made in mimicking the clinical progress of human cancer in mouse models. Previously, we developed a human breast tissue-derived (HB) mouse model. Theoretically, it may mimic the interactions between "species-specific" mammary microenvironment of human origin and human breast cancer cells. However, detailed evidences are absent. The present study (in vivo, cellular, and molecular experiments) was designed to explore the regulatory role of human mammary microenvironment in the progress of human breast cancer cells. Subcutaneous (SUB), mammary fat pad (MFP), and HB mouse models were developed for in vivo comparisons. Then, the orthotopic tumor masses from three different mouse models were collected for primary culture. Finally, the biology of primary cultured human breast cancer cells was compared by cellular and molecular experiments. Results of in vivo mouse models indicated that human breast cancer cells grew better in human mammary microenvironment. Cellular and molecular experiments confirmed that primary cultured human breast cancer cells from HB mouse model showed a better proliferative and anti-apoptotic biology than those from SUB to MFP mouse models. Meanwhile, primary cultured human breast cancer cells from HB mouse model also obtained the migratory and invasive biology for "species-specific" tissue metastasis to human tissues. Comprehensive analyses suggest that "species-specific" mammary microenvironment of human origin better regulates the biology of human breast cancer cells in our humanized mouse model of breast cancer, which is more consistent with the clinical progress of human breast cancer.

  19. Effects of the thymic microenvironment on autoantibody production in (NZB X NZW)F1 mice

    International Nuclear Information System (INIS)

    Huston, D.P.; Smathers, P.A.; Reeves, J.P.; Steinberg, A.D.

    1983-01-01

    The effects of the thymic microenvironment on autoantibody production in (NZB X NZW)F1 mice were studied. Neonatally thymectomized male and female F1 mice reconstituted with a parental or F1-irradiated thymic lobe were compared to nonreconstituted and sham-thymectomized controls. While maleness retarded the spontaneous production of ss- and ds-DNA antibodies, thymic grafts did not suppress antibodies to ss-DNA in either sex, but did suppress the production of antibodies to ds-DNA in female mice. A unique property of NZB thymic grafts was the inability to suppress anti-RBC antibodies in male mice. Thus, (i) the gender of the F1 recipient was the most important determinant of production of antibodies to ss-DNA, (ii) either maleness or the thymic microenvironment could retard production of anti-ds-DNA antibodies, and (iii) both gender and the thymic microenvironment were important in the regulation of anti-RBC antibody production. Since the administration of thymosin did not suppress autoantibody production, the effects of the thymic grafts was not solely via thymic hormone production. These studies suggest that sex hormones and/or the thymic microenvironment can exert a suppressive effect on autoantibody production and that autoantibodies differ in their susceptibility to such suppression

  20. Bed Microenvironment in Hospital Patient Rooms with Natural or Mechanical Ventilation

    DEFF Research Database (Denmark)

    Melikov, Arsen Krikor; Li, Yuguo; Georgiev, Emanuil

    2012-01-01

    We studied how to provide patients in bed with thermally comfortable microenvironment in both naturally and mechanically ventilated hospital rooms for both winter and summer seasons. A climate chamber was used to resemble a hospital room and thermal manikin to simulate a patient lying in a bed...

  1. Stromal Cells and Integrins: Conforming to the Needs of the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Aimee Alphonso

    2009-12-01

    Full Text Available The microenvironment of a tumor is constituted of a heterogenous population of stromal cells, extracellular matrix components, and secreted factors, all of which make the tumor microenvironment distinct from that of normal tissue. Unlike healthy cells, tumor cells require these unique surroundings to metastasize, spread, and form a secondary tumor at a distant site. In this review, we discuss that stromal cells such as fibroblasts and immune cells including macrophages, their secreted factors, such as vascular endothelial growth factor, transforming growth factor β, and various chemokines, and the integrins that connect the various cell types play a particularly vital role in the survival of a growing tumor mass. Macrophages and fibroblasts are uniquely plastic cells because they are not only able to switch from tumor suppressing to tumor supporting phenotypes but also able to adopt various tumor-supporting functions based on their location within the microenvironment. Integrins serve as the backbone for all of these prometastatic operations because their function as cell-cell and cell-matrix signal transducers are important for the heterogenous components of the microenvironment to communicate.

  2. 3D bioprinting: improving in vitro models of metastasis with heterogeneous tumor microenvironments

    Directory of Open Access Journals (Sweden)

    Jacob L. Albritton

    2017-01-01

    Full Text Available Even with many advances in treatment over the past decades, cancer still remains a leading cause of death worldwide. Despite the recognized relationship between metastasis and increased mortality rate, surprisingly little is known about the exact mechanism of metastatic progression. Currently available in vitro models cannot replicate the three-dimensionality and heterogeneity of the tumor microenvironment sufficiently to recapitulate many of the known characteristics of tumors in vivo. Our understanding of metastatic progression would thus be boosted by the development of in vitro models that could more completely capture the salient features of cancer biology. Bioengineering groups have been working for over two decades to create in vitro microenvironments for application in regenerative medicine and tissue engineering. Over this time, advances in 3D printing technology and biomaterials research have jointly led to the creation of 3D bioprinting, which has improved our ability to develop in vitro models with complexity approaching that of the in vivo tumor microenvironment. In this Review, we give an overview of 3D bioprinting methods developed for tissue engineering, which can be directly applied to constructing in vitro models of heterogeneous tumor microenvironments. We discuss considerations and limitations associated with 3D printing and highlight how these advances could be harnessed to better model metastasis and potentially guide the development of anti-cancer strategies.

  3. Microsensor measurements of the external and internal microenvironment of Fucus vesiculosus

    DEFF Research Database (Denmark)

    Spilling, Kristian; Titelman, Josefin; Greve, Tina M.

    2010-01-01

    We investigated the O2, pH, and irradiance microenvironment in and around the tissue of the brown alga Fucus vesiculosus L. using microsensors. Microsensors are ideal tools for gaining new insights into what limits and controls macroalgal activity and growth at very fine spatial (

  4. Co-Roman domination in graphs

    Indian Academy of Sciences (India)

    2Department of Computer Science, Liverpool Hope University, Liverpool, UK. 3Department of Computer .... such as Roman domination, weak Roman domination and secure domination, which have been investigated by ... A foolproof secure dominating function (FSDF) is a safe function f = (V0,V1) such that for each u ∈ V0 ...

  5. Yeast-expressed recombinant As16 protects mice against Ascaris suum infection through induction of a Th2-skewed immune response.

    Science.gov (United States)

    Wei, Junfei; Versteeg, Leroy; Liu, Zhuyun; Keegan, Brian; Gazzinelli-Guimarães, Ana Clara; Fujiwara, Ricardo T; Briggs, Neima; Jones, Kathryn M; Strych, Ulrich; Beaumier, Coreen M; Bottazzi, Maria Elena; Hotez, Peter J; Zhan, Bin

    2017-07-01

    Ascariasis remains the most common helminth infection in humans. As an alternative or complementary approach to global deworming, a pan-anthelminthic vaccine is under development targeting Ascaris, hookworm, and Trichuris infections. As16 and As14 have previously been described as two genetically related proteins from Ascaris suum that induced protective immunity in mice when formulated with cholera toxin B subunit (CTB) as an adjuvant, but the exact protective mechanism was not well understood. As16 and As14 were highly expressed as soluble recombinant proteins (rAs16 and rAs14) in Pichia pastoris. The yeast-expressed rAs16 was highly recognized by immune sera from mice infected with A. suum eggs and elicited 99.6% protection against A. suum re-infection. Mice immunized with rAs16 formulated with ISA720 displayed significant larva reduction (36.7%) and stunted larval development against A. suum eggs challenge. The protective immunity was associated with a predominant Th2-type response characterized by high titers of serological IgG1 (IgG1/IgG2a > 2000) and high levels of IL-4 and IL-5 produced by restimulated splenocytes. A similar level of protection was observed in mice immunized with rAs16 formulated with alum (Alhydrogel), known to induce mainly a Th2-type immune response, whereas mice immunized with rAs16 formulated with MPLA or AddaVax, both known to induce a Th1-type biased response, were not significantly protected against A. suum infection. The rAs14 protein was not recognized by A. suum infected mouse sera and mice immunized with rAs14 formulated with ISA720 did not show significant protection against challenge infection, possibly due to the protein's inaccessibility to the host immune system or a Th1-type response was induced which would counter a protective Th2-type response. Yeast-expressed rAs16 formulated with ISA720 or alum induced significant protection in mice against A. suum egg challenge that associates with a Th2-skewed immune response

  6. Yeast-expressed recombinant As16 protects mice against Ascaris suum infection through induction of a Th2-skewed immune response.

    Directory of Open Access Journals (Sweden)

    Junfei Wei

    2017-07-01

    Full Text Available Ascariasis remains the most common helminth infection in humans. As an alternative or complementary approach to global deworming, a pan-anthelminthic vaccine is under development targeting Ascaris, hookworm, and Trichuris infections. As16 and As14 have previously been described as two genetically related proteins from Ascaris suum that induced protective immunity in mice when formulated with cholera toxin B subunit (CTB as an adjuvant, but the exact protective mechanism was not well understood.As16 and As14 were highly expressed as soluble recombinant proteins (rAs16 and rAs14 in Pichia pastoris. The yeast-expressed rAs16 was highly recognized by immune sera from mice infected with A. suum eggs and elicited 99.6% protection against A. suum re-infection. Mice immunized with rAs16 formulated with ISA720 displayed significant larva reduction (36.7% and stunted larval development against A. suum eggs challenge. The protective immunity was associated with a predominant Th2-type response characterized by high titers of serological IgG1 (IgG1/IgG2a > 2000 and high levels of IL-4 and IL-5 produced by restimulated splenocytes. A similar level of protection was observed in mice immunized with rAs16 formulated with alum (Alhydrogel, known to induce mainly a Th2-type immune response, whereas mice immunized with rAs16 formulated with MPLA or AddaVax, both known to induce a Th1-type biased response, were not significantly protected against A. suum infection. The rAs14 protein was not recognized by A. suum infected mouse sera and mice immunized with rAs14 formulated with ISA720 did not show significant protection against challenge infection, possibly due to the protein's inaccessibility to the host immune system or a Th1-type response was induced which would counter a protective Th2-type response.Yeast-expressed rAs16 formulated with ISA720 or alum induced significant protection in mice against A. suum egg challenge that associates with a Th2-skewed immune

  7. On domination multisubdivision number of unicyclic graphs

    Directory of Open Access Journals (Sweden)

    Joanna Raczek

    2018-01-01

    Full Text Available The paper continues the interesting study of the domination subdivision number and the domination multisubdivision number. On the basis of the constructive characterization of the trees with the domination subdivision number equal to 3 given in [H. Aram, S.M. Sheikholeslami, O. Favaron, Domination subdivision number of trees, Discrete Math. 309 (2009, 622-628], we constructively characterize all connected unicyclic graphs with the domination multisubdivision number equal to 3. We end with further questions and open problems.

  8. Microfluidic Biopsy Trapping Device for the Real-Time Monitoring of Tumor Microenvironment.

    Directory of Open Access Journals (Sweden)

    Angela Babetski Holton

    Full Text Available The tumor microenvironment is composed of cellular and stromal components such as tumor cells, mesenchymal cells, immune cells, cancer associated fibroblasts and the supporting extracellular matrix. The tumor microenvironment provides crucial support for growth and progression of tumor cells and affects tumor response to therapeutic interventions. To better understand tumor biology and to develop effective cancer therapeutic agents it is important to develop preclinical platforms that can faithfully recapitulate the tumor microenvironment and the complex interaction between the tumor and its surrounding stromal elements. Drug studies performed in vitro with conventional two-dimensional cancer cell line models do not optimally represent clinical drug response as they lack true tumor heterogeneity and are often performed in static culture conditions lacking stromal tumor components that significantly influence the metabolic activity and proliferation of cells. Recent microfluidic approaches aim to overcome such obstacles with the use of cell lines derived in artificial three-dimensional supportive gels or micro-chambers. However, absence of a true tumor microenvironment and full interstitial flow, leads to less than optimal evaluation of tumor response to drug treatment. Here we report a continuous perfusion microfluidic device coupled with microscopy and image analysis for the assessment of drug effects on intact fresh tumor tissue. We have demonstrated that fine needle aspirate biopsies obtained from patient-derived xenograft models of adenocarcinoma of the lung can successfully be analyzed for their response to ex vivo drug treatment within this biopsy trapping microfluidic device, wherein a protein kinase C inhibitor, staurosporine, was used to assess tumor cell death as a proof of principle. This approach has the potential to study tumor tissue within its intact microenvironment to better understand tumor response to drug treatments and

  9. Probing the electrostatics of active site microenvironments along the catalytic cycle for Escherichia coli dihydrofolate reductase.

    Science.gov (United States)

    Liu, C Tony; Layfield, Joshua P; Stewart, Robert J; French, Jarrod B; Hanoian, Philip; Asbury, John B; Hammes-Schiffer, Sharon; Benkovic, Stephen J

    2014-07-23

    Electrostatic interactions play an important role in enzyme catalysis by guiding ligand binding and facilitating chemical reactions. These electrostatic interactions are modulated by conformational changes occurring over the catalytic cycle. Herein, the changes in active site electrostatic microenvironments are examined for all enzyme complexes along the catalytic cycle of Escherichia coli dihydrofolate reductase (ecDHFR) by incorporation of thiocyanate probes at two site-specific locations in the active site. The electrostatics and degree of hydration of the microenvironments surrounding the probes are investigated with spectroscopic techniques and mixed quantum mechanical/molecular mechanical (QM/MM) calculations. Changes in the electrostatic microenvironments along the catalytic environment lead to different nitrile (CN) vibrational stretching frequencies and (13)C NMR chemical shifts. These environmental changes arise from protein conformational rearrangements during catalysis. The QM/MM calculations reproduce the experimentally measured vibrational frequency shifts of the thiocyanate probes across the catalyzed hydride transfer step, which spans the closed and occluded conformations of the enzyme. Analysis of the molecular dynamics trajectories provides insight into the conformational changes occurring between these two states and the resulting changes in classical electrostatics and specific hydrogen-bonding interactions. The electric fields along the CN axes of the probes are decomposed into contributions from specific residues, ligands, and solvent molecules that make up the microenvironments around the probes. Moreover, calculation of the electric field along the hydride donor-acceptor axis, along with decomposition of this field into specific contributions, indicates that the cofactor and substrate, as well as the enzyme, impose a substantial electric field that facilitates hydride transfer. Overall, experimental and theoretical data provide evidence for

  10. Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma.

    Science.gov (United States)

    Pham, Christina D; Flores, Catherine; Yang, Changlin; Pinheiro, Elaine M; Yearley, Jennifer H; Sayour, Elias J; Pei, Yanxin; Moore, Colin; McLendon, Roger E; Huang, Jianping; Sampson, John H; Wechsler-Reya, Robert; Mitchell, Duane A

    2016-02-01

    Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice. Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8(+) PD-1(+) T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1(+) peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3(+) T cells within the tumor microenvironment. This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment. ©2015 American Association for Cancer Research.

  11. Metabarcoding of the kombucha microbial community grown in different microenvironments.

    Science.gov (United States)

    Reva, Oleg N; Zaets, Iryna E; Ovcharenko, Leonid P; Kukharenko, Olga E; Shpylova, Switlana P; Podolich, Olga V; de Vera, Jean-Pierre; Kozyrovska, Natalia O

    2015-12-01

    Introducing of the DNA metabarcoding analysis of probiotic microbial communities allowed getting insight into their functioning and establishing a better control on safety and efficacy of the probiotic communities. In this work the kombucha poly-microbial probiotic community was analysed to study its flexibility under different growth conditions. Environmental DNA sequencing revealed a complex and flexible composition of the kombucha microbial culture (KMC) constituting more bacterial and fungal organisms in addition to those found by cultural method. The community comprised bacterial and yeast components including cultured and uncultivable microorganisms. Culturing the KMC under different conditions revealed the core part of the community which included acetobacteria of two genera Komagataeibacter (former Gluconacetobacter) and Gluconobacter, and representatives of several yeast genera among which Brettanomyces/Dekkera and Pichia (including former Issatchenkia) were dominant. Herbaspirillum spp. and Halomonas spp., which previously had not been described in KMC, were found to be minor but permanent members of the community. The community composition was dependent on the growth conditions. The bacterial component of KMC was relatively stable, but may include additional member-lactobacilli. The yeast species composition was significantly variable. High-throughput sequencing showed complexity and variability of KMC that may affect the quality of the probiotic drink. It was hypothesized that the kombucha core community might recruit some environmental bacteria, particularly lactobacilli, which potentially may contribute to the fermentative capacity of the probiotic drink. As many KMC-associated microorganisms cannot be cultured out of the community, a robust control for community composition should be provided by using DNA metabarcoding.

  12. IL-33 Receptor-Expressing Regulatory T Cells Are Highly Activated, Th2 Biased and Suppress CD4 T Cell Proliferation through IL-10 and TGFβ Release.

    Directory of Open Access Journals (Sweden)

    Julia Siede

    Full Text Available Immunomodulatory Foxp3+ regulatory T cells (Tregs form a heterogeneous population consisting of subsets with different activation states, migratory properties and suppressive functions. Recently, expression of the IL-33 receptor ST2 was shown on Tregs in inflammatory settings. Here we report that ST2 expression identifies highly activated Tregs in mice even under homeostatic conditions. ST2+ Tregs preferentially accumulate at non-lymphoid sites, likely mediated by their high expression of several chemokine receptors facilitating tissue homing. ST2+ Tregs exhibit a Th2-biased character, expressing GATA-3 and producing the Th2 cytokines IL-5 and IL-13 -especially in response to IL-33. Yet, IL-33 is dispensable for the generation and maintenance of these cells in vivo. Furthermore, ST2+ Tregs are superior to ST2- Tregs in suppressing CD4+ T cell proliferation in vitro independent of IL-33. This higher suppressive capacity is partially mediated by enhanced production and activation of the anti-inflammatory cytokines IL-10 and TGFβ. Thus, ST2 expression identifies a highly activated, strongly suppressive Treg subset preferentially located in non-lymphoid tissues. Here ST2+ Tregs may be well positioned to immediately react to IL-33 alarm signals. Their specific properties may render ST2+ Tregs useful targets for immunomodulatory therapies.

  13. Prospective study in a porcine model of sarcoptes scabiei indicates the association of Th2 and Th17 pathways with the clinical severity of scabies.

    Science.gov (United States)

    Mounsey, Kate E; Murray, Hugh C; Bielefeldt-Ohmann, Helle; Pasay, Cielo; Holt, Deborah C; Currie, Bart J; Walton, Shelley F; McCarthy, James S

    2015-03-01

    Understanding of scabies immunopathology has been hampered by the inability to undertake longitudinal studies in humans. Pigs are a useful animal model for scabies, and show clinical and immunologic changes similar to those in humans. Crusted scabies can be readily established in pigs by treatment with the glucocorticoid dexamethasone (Dex). Prospective study of 24 pigs in four groups: a) Scabies+/Dex+, b) Scabies+/Dex-, c) Scabies-/Dex+ and d) Scabies-/Dex-. Clinical symptoms were monitored. Histological profiling and transcriptional analysis of skin biopsies was undertaken to compare changes in cell infiltrates and representative cytokines. A range of clinical responses to Sarcoptes scabiei were observed in Dex treated and non-immunosuppressed pigs. An association was confirmed between disease severity and transcription of the Th2 cytokines IL-4 and IL-13, and up-regulation of the Th17 cytokines IL-17 and IL-23 in pigs with crusted scabies. Immunohistochemistry revealed marked infiltration of lymphocytes and mast cells, and strong staining for IL-17. While an allergic Th2 type response to scabies has been previously described, these results suggest that IL-17 related pathways may also contribute to immunopathology of crusted scabies. This may lead to new strategies to protect vulnerable subjects from contracting recurrent crusted scabies.

  14. [Effects and mechanism of Angelicae Sinensis Radix on Th1/Th2 and Th17/Treg in mice with asthma and Yin deficiency syndrome].

    Science.gov (United States)

    Ma, Ting-Ting; Feng, Xing-Zhong; Wang, Xue-Yan

    2017-02-01

    Angelicae Sinensis Radix, with nourishing Yin, promoting blood circulation, and moisturizing dryness functions, is commonly used in clinical medicine. In order to investigate the effects and mechanism of Angelica sinensis(AS) on Th1/Th2 and Th17/Treg in mice with asthma and Yin deficiency syndrome, asthmatic and Yin deficiency syndrome Balb/c mice models were established by injecting and inhaling ovalbumin(OVA) and thyroxin. The models were treated with dexamethasone(DXM), AS extract and AS extract+DXM, respectively. Pathological examination of lung tissues was conducted by HE staining, and ELISA was used to detect the levels of IL-4, IL-17, IFN-γ, TGF-β as well as retinoic acid receptor-related orphan receptor (RORγt). Results showed that AS could significantly improve the situation of inflammation infiltration, increase ratios of IFN-γ/IL-4 and TGF-β/IL-17, decrease the levels of RORγt in lung tissues. The AS+DXM group showed a best treatment effect. The results indicated that AS played a therapeutic role for asthma with Yin deficiency syndrome and improved airway inflammation by inhibiting the expression of RORγt in lung tissues and regulating the balance of Th1/Th2 and Th17/Treg. Copyright© by the Chinese Pharmaceutical Association.

  15. The Anti-Allergic Rhinitis Effect of Traditional Chinese Medicine of Shenqi by Regulating Mast Cell Degranulation and Th1/Th2 Cytokine Balance.

    Science.gov (United States)

    Shao, Yang-Yang; Zhou, Yi-Ming; Hu, Min; Li, Jin-Ze; Chen, Cheng-Juan; Wang, Yong-Jiang; Shi, Xiao-Yun; Wang, Wen-Jie; Zhang, Tian-Tai

    2017-03-22

    Shenqi is a traditional Chinese polyherbal medicine has been widely used for the treatment of allergic rhinitis (AR). The aim of this study was to investigate the anti-allergic rhinitis activity of Shenqi and explore its underlying molecular mechanism. Ovalbumin (OVA)-induced allergic rhinitis rat model was used to evaluate the anti-allergic rhinitis effect of Shenqi. The effect of Shenqi on IgE-mediated degranulation was measured using rat basophilic leukemia (RBL-2H3) cells. Primary spleen lymphocytes were isolated to investigate the anti-allergic mechanism of Shenqi by detecting the expression of transcription factors via Western blot and the level of cytokines (IL-4 and IFN-γ) via ELISA. In OVA-induced AR rat models, Shenqi relieved the allergic rhinitis symptoms, inhibited the histopathological changes of nasal mucosa, and reduced the levels of IL-4 and IgE. The results from the in vitro study certified that Shenqi inhibited mast cell degranulation. Furthermore, the results of GATA3, T-bet, p-STAT6, and SOCS1 expression and production of IFN-γ and IL-4 demonstrated that Shenqi balanced the ratio of Th1/Th2 (IFN-γ/IL-4) in OVA-stimulated spleen lymphocytes. In conclusion, these results suggest that Shenqi exhibits an obvious anti-allergic effect by suppressing the mast cell-mediated allergic response and by improving the imbalance of Th1/Th2 ratio in allergic rhinitis.

  16. Hypertension is associated with serologically active disease in patients with systemic lupus erythematosus: role of increased Th1/Th2 ratio and oxidative stress.

    Science.gov (United States)

    Lozovoy, M A B; Simão, A N C; Morimoto, H K; Iryioda, T M V; Panis, C; Reiche, E M V; Borelli, S D; Oliveira, S R; Cecchini, R; Dichi, I

    2014-01-01

    To determine whether disease activity verified by laboratorial parameters is associated with a higher frequency of hypertension in patients with systemic lupus erythematosus (SLE) without renal impairment and to investigate factors that could influence this hypertension. This study included 102 controls, 70 patients with inactive SLE, and 53 patients with active SLE without renal impairment. We evaluated T helper type 1 (Th1)/Th2 lineage cytokines, nitric oxide (NO), insulin resistance (IR), and oxidative stress. Patients with active SLE had a higher probability of developing hypertension compared to controls [odds ratio (OR) 3.833, 95% confidence interval (CI) 1.806-8.137, p oxidation was significantly higher in patients with active SLE than in the control group and in patients with inactive SLE (p high blood pressure (43.4%) compared with patients with inactive SLE (25.7%) and controls (16.7%). Hypertension was associated with serologically active disease and was influenced by an increased Th1/Th2 ratio and oxidative stress.

  17. Effect of thymosin alpha-1 on subpopulations of Th1, Th2, Th17, and regulatory T cells (Tregs) in vitro

    International Nuclear Information System (INIS)

    Yang, Xia; Qian, Feng; He, Hai-Yang; Liu, Kai-Jun; Lan, Yuan-Zhi; Ni, Bing; Tian, Yi; Fu, Xiao-Lan; Zhang, Ji; Shen, Zi-Gang; Li, Jian; Yin, Yi; Li, Jin-Tao; Wu, Yu-Zhang

    2011-01-01

    Thymosin alpha 1 (Tα1) has been shown to have beneficial effects on numerous immune system parameters, but little is known about the effects of Tα1 on patients with gastric carcinoma. The objective of this study was to determine the effect of Tα1 on subpopulations of Th1, Th2, Th17, and regulatory T cells (Tregs) in vitro, and to evaluate its efficacy as an immunoregulatory factor in patients with gastric carcinoma. We compared the effect of Tα1 on the frequency of CD4 + and CD8 + T cells, especially the CD4 + CD25 + Foxp3 + Tregs in peripheral blood mononuclear cells (PBMCs) from gastric carcinoma patients (N = 35) and healthy donors (N = 22). We also analyzed the changes in the proliferation of PBMCs in response to treatment with Tα1, and examined the production of Th1, Th2, and Th17 cytokines by PBMCs and tumor-infiltrating lymphocytes. The treatment of PBMCs from gastric cancer patients, with Tα1 (50 µg/mL) alone increased the percentage of CD4+CD25+Foxp3+ (suppressive antitumor-specific Tregs) from 1.68 ± 0.697 to 2.19 ± 0.795% (P < 0.05). Our results indicate that Tα1 increases the percentage of Tregs and IL-1β, TNF-α, and IL-6 in vitro

  18. Breast regression protein-39 (BRP-39) promotes dendritic cell maturation in vitro and enhances Th2 inflammation in murine model of asthma.

    Science.gov (United States)

    Xu, Qian; Chai, Shou-jie; Qian, Ying-ying; Zhang, Min; Wang, Kai

    2012-12-01

    To determine the roles of breast regression protein-39 (BRP-39) in regulating dendritic cell maturation and in pathology of acute asthma. Mouse bone marrow-derived dendritic cells (BMDCs) were prepared, and infected with adenovirus over-expressing BRP-39. Ovalbumin (OVA)-induced murine model of acute asthma was made in female BALB/c mice by sensitizing and challenging with chicken OVA and Imject Alum. The transfected BMDCs were adoptively transferred into OVA-treated mice via intravenous injection. Airway hyperresponsiveness (AHR), inflammation and pulmonary histopathology were characterized. The expression of BRP-39 mRNA and protein was significantly increased in lung tissues of OVA-treated mice. The BMDCs infected with adenovirus BRP-39 exhibited greater maturation and higher activity in vitro. Adoptive transfer of the cells into OVA-treated mice significantly augmented OVA-induced AHR and eosinophilic inflammation. Meanwhile, BRP-39 further enhanced the production of OVA-induced Th2 cytokines IL-4, IL-5 and IL-13, but significantly attenuated OVA-induced IFN-γ production in bronchoalveolar lavage fluid. In OVA-induced murine model of acute asthma, BRP-39 is over-expressed in lung tissue and augments Th2 inflammatory response and AHR. BRP-39 promotes dendritic cell maturation in vitro. Therefore, BRP-39 may be a potential therapeutic target of asthma.

  19. Enhanced expression of PD-L1 and IFN-γ on dendritic cells is associated with BCG-induced Th2 inhibition.

    Science.gov (United States)

    Gouveia, A C C; Braga, F G; Mota, M; Silva, F M C; Brugiolo, A S S; Oliveira, E E; Ayupe, M C; Teixeira, H C; Ferreira, A P

    2017-11-01

    Accumulating evidence indicates that the exposure to Mycobacterium bovis bacillus Calmette-Guérin (BCG) prevents the development of allergy and the airway dendritic cells (DCs) may be involved in this protective effect. However, studies to better characterize the specific interactions between BCG and DCs and their role in this mycobacteria-mediated Th2 cell suppression are still ongoing. This study aimed to evaluate the effect of the neonatal BCG vaccination in the innate immune response in a mouse model of ovalbumin (OVA)-induced airway inflammation. BCG treated neonatal BALB/c mice were sensitized and challenged with aerosolized OVA. Twenty-four hours after the last challenge, samples were collected for analysis. The intranasal BCG treatment inhibited the allergic Th2-response by decreasing the allergen-induced eosinophilic inflammation, EPO activity, CCL11, IL-25, TSLP, IL-4 and IL-5 lung levels, and serum levels of IgE. Mycobacteria treatment increased lung levels of IL-10 and TGF-β, and the TLR2 and TLR4 expressions by pulmonary CD11c + CD103 + CD8α + DCs. Additionally an enhanced expression of PD-L1 was observed besides an increased production of IFN-γ by these cells. These results indicated that neonatal BCG vaccination inhibits key features of allergic airway inflammation, probably by promoting T regulatory immune response via an enhanced expression of TLR2, TLR4 and PD-L1 on DCs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Cord blood monocyte-derived inflammatory cytokines suppress IL-2 and induce nonclassic "T(H)2-type" immunity associated with development of food allergy.

    Science.gov (United States)

    Zhang, Yuxia; Collier, Fiona; Naselli, Gaetano; Saffery, Richard; Tang, Mimi L K; Allen, Katrina J; Ponsonby, Anne-Louise; Harrison, Leonard C; Vuillermin, Peter

    2016-01-13

    Food allergy is a major health burden in early childhood. Infants who develop food allergy display a proinflammatory immune profile in cord blood, but how this is related to interleukin-4 (IL-4)/T helper 2 (T(H)2)-type immunity characteristic of allergy is unknown. In a general population-derived birth cohort, we found that in infants who developed food allergy, cord blood displayed a higher monocyte to CD4(+) T cell ratio and a lower proportion of natural regulatory T cell (nT(reg)) in relation to duration of labor. CD14(+) monocytes of food-allergic infants secreted higher amounts of inflammatory cytokines (IL-1β, IL-6, and tumor necrosis factor-α) in response to lipopolysaccharide. In the presence of the mucosal cytokine transforming growth factor-β, these inflammatory cytokines suppressed IL-2 expression by CD4(+) T cells. In the absence of IL-2, inflammatory cytokines decreased the number of activated nT(reg) and diverted the differentiation of both nT(reg) and naïve CD4(+) T cells toward an IL-4-expressing nonclassical TH2 phenotype. These findings provide a mechanistic explanation for susceptibility to food allergy in infants and suggest anti-inflammatory approaches to its prevention. Copyright © 2016, American Association for the Advancement of Science.

  1. A possible mechanism in the recruitment of eosinophils and Th2 cells through CD163(+) M2 macrophages in the lesional skin of eosinophilic cellulitis.

    Science.gov (United States)

    Fujimura, Taku; Kambayashi, Yumi; Furudate, Sadanori; Kakizaki, Aya; Aiba, Setsuya

    2014-01-01

    M2 macrophages play a critical role in the recruitment of T helper 2 (Th2) regulatory T cells (Treg). To study the role of M2 macrophages and Treg cells in eosinophilic celulitis. We employed immunohistochemical staining for CD163( )and CD206 (macrophages) as well as FoxP3 (Treg), in lesional skin of four cases of eosinophilic cellulitis. CD163(+) CD206(+) M2 macrophages, which were previously reported to produce CCL17 to induce Th2 cells and Treg cells, were predominantly infiltrating the subcutaneous tissues and interstitial area of the dermis. M2 macrophages derived from PBMC showed significantly increased expression of CCL11, CCL17, CCL24 and CCL26 mRNA and production of CCL17 and CCL24, when stimulated by IL-4 or IL- 13. In addition, CCL17-producing cells and CCL24-producing cells were prominent in the lesional skin of EC. Our study sheds light on one of the possible immunological mechanisms of eosinophilic cellulitis.

  2. Effect of thymosin alpha-1 on subpopulations of Th1, Th2, Th17, and regulatory T cells (Tregs) in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xia [Institute of Immunology,Third Military Medical University, Chongqing (China); Qian, Feng [Department of General Surgery, Southwest Hospital, Third Military Medical University, Chongqing (China); He, Hai-Yang; Liu, Kai-Jun [Institute of Immunology,Third Military Medical University, Chongqing (China); Lan, Yuan-Zhi [Department of General Surgery, Southwest Hospital, Third Military Medical University, Chongqing (China); Ni, Bing; Tian, Yi; Fu, Xiao-Lan; Zhang, Ji; Shen, Zi-Gang; Li, Jian; Yin, Yi; Li, Jin-Tao; Wu, Yu-Zhang [Institute of Immunology,Third Military Medical University, Chongqing (China)

    2011-12-02

    Thymosin alpha 1 (Tα1) has been shown to have beneficial effects on numerous immune system parameters, but little is known about the effects of Tα1 on patients with gastric carcinoma. The objective of this study was to determine the effect of Tα1 on subpopulations of Th1, Th2, Th17, and regulatory T cells (Tregs) in vitro, and to evaluate its efficacy as an immunoregulatory factor in patients with gastric carcinoma. We compared the effect of Tα1 on the frequency of CD4{sup +} and CD8{sup +} T cells, especially the CD4{sup +}CD25{sup +}Foxp3{sup +} Tregs in peripheral blood mononuclear cells (PBMCs) from gastric carcinoma patients (N = 35) and healthy donors (N = 22). We also analyzed the changes in the proliferation of PBMCs in response to treatment with Tα1, and examined the production of Th1, Th2, and Th17 cytokines by PBMCs and tumor-infiltrating lymphocytes. The treatment of PBMCs from gastric cancer patients, with Tα1 (50 µg/mL) alone increased the percentage of CD4+CD25+Foxp3+ (suppressive antitumor-specific Tregs) from 1.68 ± 0.697 to 2.19 ± 0.795% (P < 0.05). Our results indicate that Tα1 increases the percentage of Tregs and IL-1β, TNF-α, and IL-6 in vitro.

  3. Stat6-dependent inhibition of Mincle expression in mouse and human antigen-presenting cells by the Th2 cytokine IL-4

    Directory of Open Access Journals (Sweden)

    Thomas Hupfer

    2016-10-01

    Full Text Available The C-type lectin receptors (CLR Mincle, Mcl and Dectin-2 bind mycobacterial and fungal cell wall glycolipids and carbohydrates. Recently, we described that expression of these CLR is down-regulated during differentiation of human monocytes to dendritic cells (DC in the presence of GM-CSF and IL-4. Here, we demonstrate that the Th2 cytokine IL-4 specifically inhibits expression of Mincle, Mcl and Dectin-2in human APC. This inhibitory effect of IL-4 was observed across species, as murine macrophages and DC treated with IL-4 also down-regulated these receptors. IL-4 blocked up-regulation of Mincle and Mcl mRNA expression and cell surface protein by murine macrophages in response to the Mincle ligand Trehalose-6,6-dibehenate (TDB, whereas the TLR4 ligand LPS overcame inhibition by IL-4. Functionally, down-regulation of Mincle expression by IL-4 was accompanied by reduced cytokine production upon stimulation with TDB. These inhibitory effects of IL-4 were dependent on the transcription factor Stat6. Together, our results show that the key Th2 cytokine IL-4 exerts a negative effect on the expression of Mincle and other Dectin-2 cluster CLR in mouse and human macrophages and DC, which may render these sentinel cells less vigilant for sensing mycobacterial and fungal ligands.

  4. Prospective study in a porcine model of sarcoptes scabiei indicates the association of Th2 and Th17 pathways with the clinical severity of scabies.

    Directory of Open Access Journals (Sweden)

    Kate E Mounsey

    2015-03-01

    Full Text Available BACKGROUND: Understanding of scabies immunopathology has been hampered by the inability to undertake longitudinal studies in humans. Pigs are a useful animal model for scabies, and show clinical and immunologic changes similar to those in humans. Crusted scabies can be readily established in pigs by treatment with the glucocorticoid dexamethasone (Dex. METHODOLOGY/ PRINCIPAL FINDINGS: Prospective study of 24 pigs in four groups: a Scabies+/Dex+, b Scabies+/Dex-, c Scabies-/Dex+ and d Scabies-/Dex-. Clinical symptoms were monitored. Histological profiling and transcriptional analysis of skin biopsies was undertaken to compare changes in cell infiltrates and representative cytokines. A range of clinical responses to Sarcoptes scabiei were observed in Dex treated and non-immunosuppressed pigs. An association was confirmed between disease severity and transcription of the Th2 cytokines IL-4 and IL-13, and up-regulation of the Th17 cytokines IL-17 and IL-23 in pigs with crusted scabies. Immunohistochemistry revealed marked infiltration of lymphocytes and mast cells, and strong staining for IL-17. CONCLUSIONS/ SIGNIFICANCE: While an allergic Th2 type response to scabies has been previously described, these results suggest that IL-17 related pathways may also contribute to immunopathology of crusted scabies. This may lead to new strategies to protect vulnerable subjects from contracting recurrent crusted scabies.

  5. Direct laser writing by two-photon polymerization as a tool for developing microenvironments for evaluation of bacterial growth

    International Nuclear Information System (INIS)

    Otuka, A.J.G.; Corrêa, D.S.; Fontana, C.R.; Mendonça, C.R.

    2014-01-01

    Monitoring bacteria growth and motion in environments is fundamental to understand, for instance, how they proliferate and contaminate organism. Therefore, techniques to fabricate microenvironments for in situ and in vivo studies are interesting for that purpose. In this work we used two-photon polymerization to fabricate microenvironments and, as a proof of principle, we demonstrated the development of the bacteria ATCC 25922 Escherichia coli (E. coli) into the microstructure surroundings. Two varieties of polymeric microenvironments are presented: (i) a microenvironment doped at specific site with ciprofloxacin, an antibiotic typically used in the treatment of diseases caused by E. coli and (ii) micro-fences, which serve as traps for bacteria. These microenvironments, fabricated by two-photon polymerization, may be a potential platform for drug delivery system, by promoting or inhibiting the growth of bacteria in specific biological or synthetic sites. - Highlights: • Microenvironments were fabricated by two-photon polymerization. • We demonstrated the development of Escherichia coli into the microstructure surroundings. • Microenvironment doped with the antibiotic ciprofloxacin was fabricated. • Micro-fences, which serve as traps for bacteria, were also produced

  6. Direct laser writing by two-photon polymerization as a tool for developing microenvironments for evaluation of bacterial growth

    Energy Technology Data Exchange (ETDEWEB)

    Otuka, A.J.G. [Instituto de Física de São Carlos, Universidade de São Paulo, CP.369, 13560-970 São Carlos, SP (Brazil); Corrêa, D.S. [Laboratório Nacional de Nanotecnologia para o Agronegócio (LNNA), Embrapa Instrumentação, Rua XV de Novembro, 1452, CP.741, 13560-970 São Carlos, SP (Brazil); Fontana, C.R. [Department of Clinical Analysis, School of Pharmaceutical Sciences, University of São Paulo State (UNESP), 1621 Expedicionarios do Brasil Street, Araraquara, Sao Paulo 14801-960 (Brazil); Mendonça, C.R., E-mail: crmendon@ifsc.usp.br [Instituto de Física de São Carlos, Universidade de São Paulo, CP.369, 13560-970 São Carlos, SP (Brazil)

    2014-02-01

    Monitoring bacteria growth and motion in environments is fundamental to understand, for instance, how they proliferate and contaminate organism. Therefore, techniques to fabricate microenvironments for in situ and in vivo studies are interesting for that purpose. In this work we used two-photon polymerization to fabricate microenvironments and, as a proof of principle, we demonstrated the development of the bacteria ATCC 25922 Escherichia coli (E. coli) into the microstructure surroundings. Two varieties of polymeric microenvironments are presented: (i) a microenvironment doped at specific site with ciprofloxacin, an antibiotic typically used in the treatment of diseases caused by E. coli and (ii) micro-fences, which serve as traps for bacteria. These microenvironments, fabricated by two-photon polymerization, may be a potential platform for drug delivery system, by promoting or inhibiting the growth of bacteria in specific biological or synthetic sites. - Highlights: • Microenvironments were fabricated by two-photon polymerization. • We demonstrated the development of Escherichia coli into the microstructure surroundings. • Microenvironment doped with the antibiotic ciprofloxacin was fabricated. • Micro-fences, which serve as traps for bacteria, were also produced.

  7. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth

    Science.gov (United States)

    Yao, Jun; Lowery, Frank J.; Zhang, Qingling; Huang, Wen-Chien; Li, Ping; Li, Min; Wang, Xiao; Zhang, Chenyu; Wang, Hai; Ellis, Kenneth; Cheerathodi, Mujeeburahiman; McCarty, Joseph H.; Palmieri, Diane; Saunus, Jodi; Lakhani, Sunil; Huang, Suyun; Sahin, Aysegul A.; Aldape, Kenneth D.; Steeg, Patricia S.; Yu, Dihua

    2016-01-01

    Summary Development of life-threatening cancer metastases at distant organs requires disseminated tumor cells’ adaptation to and co-evolution with the drastically different microenvironments of metastatic sites1. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs2. Clearly, the dynamic interplay between metastatic tumor cells and extrinsic signals at individual metastatic organ sites critically impacts the subsequent metastatic outgrowth3,4. Yet, it is unclear when and how disseminated tumor cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that primary tumor cells with normal expression of PTEN, an important tumor suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. PTEN level in PTEN-loss brain metastatic tumor cells is restored after leaving brain microenvironment. This brain microenvironment-dependent, reversible PTEN mRNA and protein down-regulation is epigenetically regulated by microRNAs (miRNAs) from astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting miRNAs to metastatic tumor cells, while astrocyte-specific depletion of PTEN-targeting miRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumor cells leads to an increased secretion of cytokine chemokine (C-C motif) ligand 2 (CCL2), which recruits Iba1+ myeloid cells that reciprocally enhance outgrowth of brain metastatic tumor cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumor cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic

  8. Dominant drivers of business students

    Directory of Open Access Journals (Sweden)

    Radu Cătălina

    2017-07-01

    Full Text Available Taibi Kahler wrote in 1974 a theory about five main drivers that could explain people’s motivation and a series of positive and negative behavior patterns: Be Strong, Be Perfect, Hurry Up, Try Hard and Please People. Of course, we consider there is no absolute positive or negative behavior, since (1 everything needs to be analyzed by taking into account the context and (2 any behavior pattern can mean a series of advantages as long as people understand their own values, beliefs, attitudes and behaviors. It would be interesting to link Kahler’s drivers to the educational process, in order to be able to adapt our courses and our teaching styles to students’ requirements and also to the requirements in the labor market. Our paper is built on literature review and a questionnaire applied to a sample of 607 students in Bucharest University of Economic Studies, Romania. Information was processed with Microsoft Excel 2013, in order to look at the main working styles our students have, at the main explanations for the differences between them and in order to test a series of hypotheses. We were interested to look at the main traits of the current generation of students in our university: dominant drivers, roles of managers and specialists, the attractiveness of the entrepreneurial career path, etc. and at a series of patterns (i.e. gender-related differences. We consider results of this study are useful both for teaching and research purposes. In terms of teaching, we plan to adapt our educational methods in order to improve the educational process.

  9. On The Roman Domination Stable Graphs

    Directory of Open Access Journals (Sweden)

    Hajian Majid

    2017-11-01

    Full Text Available A Roman dominating function (or just RDF on a graph G = (V,E is a function f : V → {0, 1, 2} satisfying the condition that every vertex u for which f(u = 0 is adjacent to at least one vertex v for which f(v = 2. The weight of an RDF f is the value f(V (G = Pu2V (G f(u. The Roman domination number of a graph G, denoted by R(G, is the minimum weight of a Roman dominating function on G. A graph G is Roman domination stable if the Roman domination number of G remains unchanged under removal of any vertex. In this paper we present upper bounds for the Roman domination number in the class of Roman domination stable graphs, improving bounds posed in [V. Samodivkin, Roman domination in graphs: the class RUV R, Discrete Math. Algorithms Appl. 8 (2016 1650049].

  10. Mould-sensitized adults have lower Th2 cytokines and a higher prevalence of asthma than those sensitized to other aeroallergens.

    Science.gov (United States)

    Matheson, M C; Reece, J C; Kandane-Rathnayake, R K; Tang, M L K; Simpson, J A; Feather, I H; Southey, M C; Tsimiklis, H; Hopper, J L; Morrison, S C; Giles, G G; Walters, E H; Dharmage, S C

    2016-12-01

    Evidence suggests that specific allergen sensitizations are associated with different allergic diseases which may reflect different underlying immune profiles. We aimed to examine the cytokine profiles of individuals sensitized to eight common aeroallergens. We used data from the Tasmanian Longitudinal Health Study a population-based cohort study of 45-year-olds. Serum cytokines (IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α) were measured in 1157 subjects using the LINCOplex assays. Participants underwent skin prick testing for house dust mite, cat, grasses and moulds. Multivariable linear regression was used to compare serum cytokine levels between sensitized and nonatopic subjects. The prevalence of allergic sensitization to any aeroallergen was 51% (95% CI 47-54). Being sensitized to any aeroallergen was strongly associated with current asthma (OR = 3.7, 95% CI 2.6-5.3), and being sensitized to any moulds was associated with a very high risk of current asthma (OR = 6.40, 95% CI 4.06-10.1). The geometric mean (GM) levels of Th2 cytokines (IL-4, IL-5 and IL-6) for adults sensitized to Cladosporium were significantly lower than the levels for nonatopic individuals (IL-4 ratio of GMs = 0.25, 95% CI 0.10-0.62, P = 0.003; IL-5 GM = 0.55, 95% CI 0.30-0.99, P = 0.05; and IL-6 GM = 0.50, 95% CI 0.24-1.07, P = 0.07). Individuals sensitized to other aeroallergens all showed elevated Th2 cytokine levels. Our study is the first large population-based study to demonstrate reduced Th2 cytokines levels in people sensitized to mould. Underlying biological mechanisms driving allergic inflammatory responses in adults sensitized to moulds may differ from those sensitized to other aeroallergens. These findings suggest that it may be necessary to tailor treatments in individuals sensitized to moulds compared with other aeroallergens in order to optimize outcomes. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

    Directory of Open Access Journals (Sweden)

    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

  12. 5 CFR 532.305 - Dominant industry.

    Science.gov (United States)

    2010-01-01

    ... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Dominant industry. 532.305 Section 532... SYSTEMS Determining Rates for Principal Types of Positions § 532.305 Dominant industry. (a)(1) A specialized industry is a “dominant industry” if the number of wage employees in the wage area who are subject...

  13. Dominant limb asymmetry associated with prospective injury ...

    African Journals Online (AJOL)

    The purpose of the study was to identify associations between dominant lower limb asymmetry in unanticipated agility performance and prospective injury occurrence. Female netball players (N=24) performed unanticipated 180° turn agility sprints on both the dominant and non-dominant legs interspersed with an additional ...

  14. Co-Roman domination in graphs

    Indian Academy of Sciences (India)

    The basic complexity question of the decision problem for the co-Roman domination number takes the following form: Co-Roman Domination (CRDM). Instance. A nontrivial connected graph G = (V,E) and a positive integer k. Question. Does G have a co-Roman dominating function f with w(f ) ≤ k? We proceed to prove that ...

  15. The role of the tissue microenvironment in the regulation of cancer cell motility and invasion

    Directory of Open Access Journals (Sweden)

    Brábek Jan

    2010-09-01

    Full Text Available Abstract During malignant neoplastic progression the cells undergo genetic and epigenetic cancer-specific alterations that finally lead to a loss of tissue homeostasis and restructuring of the microenvironment. The invasion of cancer cells through connective tissue is a crucial prerequisite for metastasis formation. Although cell invasion is foremost a mechanical process, cancer research has focused largely on gene regulation and signaling that underlie uncontrolled cell growth. More recently, the genes and signals involved in the invasion and transendothelial migration of cancer cells, such as the role of adhesion molecules and matrix degrading enzymes, have become the focus of research. In this review we discuss how the structural and biomechanical properties of extracellular matrix and surrounding cells such as endothelial cells influence cancer cell motility and invasion. We conclude that the microenvironment is a critical determinant of the migration strategy and the efficiency of cancer cell invasion.

  16. The Healthy and Diseased Microenvironments Regulate Oligodendrocyte Properties: Implications for Regenerative Medicine.

    Science.gov (United States)

    Leferink, Prisca S; Heine, Vivi M

    2018-01-01

    White matter disorders are characterized by deficient myelin or myelin loss, lead to a range of neurologic dysfunctions, and can result in early death. Oligodendrocytes, which are responsible for white matter formation, are the first targets for treatment. However, many studies indicate that failure of white matter repair goes beyond the intrinsic incapacity of oligodendrocytes to (re)generate myelin and that failed interactions with neighboring cells or factors in the diseased microenvironment can underlie white matter defects. Moreover, most of the white matter disorders show specific white matter pathology caused by different disease mechanisms. Herein, we review the factors within the cellular and the extracellular microenvironment regulating oligodendrocyte properties and discuss stem cell tools to identify microenvironmental factors of importance to the development of improved regenerative medicine for patients with white matter disorders. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  17. Nocardia brasiliensis induces an immunosuppressive microenvironment that favors chronic infection in BALB/c mice.

    Science.gov (United States)

    Rosas-Taraco, Adrian G; Perez-Liñan, Amira R; Bocanegra-Ibarias, Paola; Perez-Rivera, Luz I; Salinas-Carmona, Mario C

    2012-07-01

    Nocardia brasiliensis is an intracellular microorganism and the most common etiologic agent of actinomycetoma in the Americas. Several intracellular pathogens induce an immunosuppressive microenvironment through increases in CD4+ Foxp3+ regulatory T cells (Treg), thus downregulating other T-cell subpopulations and assuring survival in the host. In this study, we determined whether N. brasiliensis modulates T-lymphocyte responses and their related cytokine profiles in a murine experimental model. We also examined the relationship between N. brasiliensis immunomodulation and pathogenesis and bacterial survival. In early infection, Th17/Tc17 cells were increased at day 3 (P 1 log) was also observed (P brasiliensis modulates the immune system to induce an immunosuppressive microenvironment that benefits its survival during the chronic stage of infection.

  18. Breathing and Cross-Infection Risk in the Microenvironment around People

    DEFF Research Database (Denmark)

    Nielsen, Peter Vilhelm; Zajas, Jan Jakub; Litewnicki, Michal

    2014-01-01

    The paper focuses on the characteristics of cross-infection risk in a room with an air distribution which creates fully mixed conditions. Several experiments are made to develop models for the flow in the microenvironment and models for the cross-infection risk. The first part of the measurements...... detailed analyses of the flow in the microenvironment of the two manikins and a study of the importance of the individual distance between the manikins. Also the importance of the activity level, difference in heights, breathing through mouth or nose is studied in details....... (breathing frequency and volume flow) and it includes a study of the influence of the thermal boundary layer of the manikin. Second part covers measurements with the use of two manikins. It is examined how one exhaling manikin can influence another regarding cross-infection risks. This study includes...

  19. Bone Marrow Cells in Acute Lymphoblastic Leukemia Create a Proinflammatory Microenvironment Influencing Normal Hematopoietic Differentiation Fates

    Directory of Open Access Journals (Sweden)

    Armando Vilchis-Ordoñez

    2015-01-01

    Full Text Available B-cell acute lymphoblastic leukemia (B-ALL is a serious public health problem in the pediatric population worldwide, contributing to 85% of deaths from childhood cancers. Understanding the biology of the disease is crucial for its clinical management and the development of therapeutic strategies. In line with that observed in other malignancies, chronic inflammation may contribute to a tumor microenvironment resulting in the damage of normal processes, concomitant to development and maintenance of neoplastic cells. We report here that hematopoietic cells from bone marrow B-ALL have the ability to produce proinflammatory and growth factors, including TNFα, IL-1β, IL-12, and GM-CSF that stimulate proliferation and differentiation of normal stem and progenitor cells. Our findings suggest an apparently distinct CD13+CD33+ population of leukemic cells contributing to a proinflammatory microenvironment that may be detrimental to long-term normal hematopoiesis within B-ALL bone marrow.

  20. Tumour microenvironment and radiation response in sarcomas originating from tumourigenic human mesenchymal stem cells

    DEFF Research Database (Denmark)

    D'Andrea, Filippo P; Safwat, Akmal Ahmed; Burns, Jorge S

    2012-01-01

    Background: Resistance to radiation therapy remains a serious impediment to cancer therapy. We previously reported heterogeneity for clonogenic survival when testing in vitro radiation resistance among single-cell derived clones from a human mesenchymal cancer stem cell model (hMSC). Here we aimed...... to determine whether this heterogeneity persisted in tumours established from these clones, and whether the response to radiation treatment was principally governed by cell-intrinsic qualities or by factors pertaining to the tumour microenvironment, such as the degree of hypoxia and vascularization. Methods......: Immune-deficient female mice were implanted on the backs with cells from one of the clones. The subsequent tumours were subjected to either radiation treatment or had the tumour microenvironment assayed, when they reached 400 mm(3). Radiation was given as a single fraction of 0-15 Gy and the degree...

  1. Nocardia brasiliensis Induces an Immunosuppressive Microenvironment That Favors Chronic Infection in BALB/c Mice

    Science.gov (United States)

    Rosas-Taraco, Adrian G.; Perez-Liñan, Amira R.; Bocanegra-Ibarias, Paola; Perez-Rivera, Luz I.

    2012-01-01

    Nocardia brasiliensis is an intracellular microorganism and the most common etiologic agent of actinomycetoma in the Americas. Several intracellular pathogens induce an immunosuppressive microenvironment through increases in CD4+ Foxp3+ regulatory T cells (Treg), thus downregulating other T-cell subpopulations and assuring survival in the host. In this study, we determined whether N. brasiliensis modulates T-lymphocyte responses and their related cytokine profiles in a murine experimental model. We also examined the relationship between N. brasiliensis immunomodulation and pathogenesis and bacterial survival. In early infection, Th17/Tc17 cells were increased at day 3 (P 1 log) was also observed (P brasiliensis modulates the immune system to induce an immunosuppressive microenvironment that benefits its survival during the chronic stage of infection. PMID:22547544

  2. The Immunomodulatory Effects of Mesenchymal Stem Cell Polarization within the Tumor Microenvironment Niche

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    Cosette M. Rivera-Cruz

    2017-01-01

    Full Text Available Mesenchymal stem cells (MSCs represent a promising tool for cell therapy, particularly for their antitumor effects. This cell population can be isolated from multiple tissue sources and also display an innate ability to home to areas of inflammation, such as tumors. Upon entry into the tumor microenvironment niche, MSCs promote or inhibit tumor progression by various mechanisms, largely through the release of soluble factors. These factors can be immunomodulatory by activating or inhibiting both the adaptive and innate immune responses. The mechanisms by which MSCs modulate the immune response are not well understood. Because of this, the relationship between MSCs and immune cells within the tumor microenvironment niche continues to be an active area of research in order to help explain the apparent contradictory findings currently available in the literature. The ongoing research aims to enhance the potential of MSCs in future therapeutic applications.

  3. Epigenetic dominance of prion conformers.

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    Eri Saijo

    2013-10-01

    Full Text Available Although they share certain biological properties with nucleic acid based infectious agents, prions, the causative agents of invariably fatal, transmissible neurodegenerative disorders such as bovine spongiform encephalopathy, sheep scrapie, and human Creutzfeldt Jakob disease, propagate by conformational templating of host encoded proteins. Once thought to be unique to these diseases, this mechanism is now recognized as a ubiquitous means of information transfer in biological systems, including other protein misfolding disorders such as those causing Alzheimer's and Parkinson's diseases. To address the poorly understood mechanism by which host prion protein (PrP primary structures interact with distinct prion conformations to influence pathogenesis, we produced transgenic (Tg mice expressing different sheep scrapie susceptibility alleles, varying only at a single amino acid at PrP residue 136. Tg mice expressing ovine PrP with alanine (A at (OvPrP-A136 infected with SSBP/1 scrapie prions propagated a relatively stable (S prion conformation, which accumulated as punctate aggregates in the brain, and produced prolonged incubation times. In contrast, Tg mice expressing OvPrP with valine (V at 136 (OvPrP-V136 infected with the same prions developed disease rapidly, and the converted prion was comprised of an unstable (U, diffusely distributed conformer. Infected Tg mice co-expressing both alleles manifested properties consistent with the U conformer, suggesting a dominant effect resulting from exclusive conversion of OvPrP-V136 but not OvPrP-A136. Surprisingly, however, studies with monoclonal antibody (mAb PRC5, which discriminates OvPrP-A136 from OvPrP-V136, revealed substantial conversion of OvPrP-A136. Moreover, the resulting OvPrP-A136 prion acquired the characteristics of the U conformer. These results, substantiated by in vitro analyses, indicated that co-expression of OvPrP-V136 altered the conversion potential of OvPrP-A136 from the S to

  4. [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.

  5. New hydrothermal synthesis and structure of Th2(PO4)2(HPO4).H2O: the first structurally characterized thorium Hydrogenphosphate.

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    Salvadó, Miguel A; Pertierra, Pilar; Bortun, Anatoly I; Trobajo, Camino; García, José R

    2005-05-16

    Th(2)(PO(4))(2)(HPO(4)).H(2)O was synthesized under wet hydrothermal conditions starting from a mixture of H(3)PO(3) and Th(NO(3))(4).5H(2)O. The crystal structure was solved by powder X-ray diffraction data. The unit cell parameters are a = 6.7023(8) Angstroms, b = 7.0150(8) Angstroms, c = 11.184(1) Angstroms, beta = 107.242(4) degrees, space group P2(1), and Z = 2. The structure consists of layers of both thorium atoms and PO(4) groups, alternating with a layer formed by HPO(4) entities and water molecules. By thermal treatment, this compound turns into Th(4)(PO(4))(4)P(2)O(7), a ceramic already described in the field of the immobilization of tetravalent actinides.

  6. Dental follicle cells rescue the regenerative capacity of periodontal ligament stem cells in an inflammatory microenvironment.

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    Jia Liu

    Full Text Available AIMS: Periodontal ligament stem cells (PDLSCs are one of the best candidates for periodontal regeneration. Their function could be impaired in periodontitis microenvironment. Dental follicle cells (DFCs, serving as precursor cells and mesenchymal stem cells, have intimate connection with PDLSCs. However, it is still unknown whether DFCs could provide a favorable microenvironment to improve the proliferation and differentiation capacity of PDLSCs from healthy subjects (HPDLSCs and patients diagnosed with periodontitis (PPDLSCs. METHODS: HPDLSCs, PPDLSCs and DFCs were harvested and identified using microscopic and flow cytometric analysis. Then, the coculture systems of DFCs/HPDLSCs and DFCs/PPDLSCs were established with 0.4 µm transwell, in which all the detection indexs were obtained from HPDLSCs and PPDLSCs. The expression of stemness-associated genes was detected by real-time PCR, and the proliferation ability was assessed using colony formation and cell cycle assays. The osteogenic differentiation capacity was evaluated by real-time PCR, western blot, ALP activity, Alizarin Red S staining and calcium level analysis, while the adipogenic differentiation capacity was determined by real-time PCR and Oil Red O staining. The cell sheet formation in vitro was observed by HE staining and SEM, and the implantation effect in vivo was evaluated using HE staining and Masson's trichrome staining. RESULTS: PPDLSCs had a greater proliferation capability but lower osteogenic and adipogenic potential than HPDLSCs. DFCs enhanced the proliferation and osteogenic/adipogenic differentiation of HPDLSCs and PPDLSCs to different degrees. Moreover, coculture with DFCs increased cell layers and extr