8 results on '"Georas, Steve N."'
Search Results
2. Developmental Exposure to a Mixture of 23 Chemicals AssociatedWith Unconventional Oil and Gas Operations Alters the Immune System of Mice.
- Author
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Boulé, Lisbeth A, Chapman, Timothy J, Hillman, Sara E, Kassotis, Christopher D, O'Dell, Colleen, Robert, Jacques, Georas, Steve N, Nagel, Susan C, and Lawrence, B Paige
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IMMUNOTOXICOLOGY ,HYDRAULIC fracturing ,ENCEPHALOMYELITIS ,T cells ,DEVELOPMENTAL toxicology ,LABORATORY mice - Abstract
Chemicals used in unconventional oil and gas (UOG) operations have the potential to cause adverse biological effects, but this has not been thoroughly evaluated. A notable knowledge gap is their impact on development and function of the immune system. Herein, we report an investigation of whether developmental exposure to a mixture of chemicals associated with UOG operations affects the development and function of the immune system. We used a previously characterized mixture of 23 chemicals associated with UOG, and which was demonstrated to affect reproductive and developmental endpoints in mice. C57Bl/6 mice were maintained throughout pregnancy and during lactation on water containing two concentrations of this 23-chemical mixture, and the immune system of male and female adult offspring was assessed. We comprehensively examined the cellularity of primary and secondary immune organs, and used three different disease models to probe potential immune effects: house dust mite-induced allergic airway disease, influenza A virus infection, and experimental autoimmune encephalomyelitis (EAE). In all three disease models, developmental exposure altered frequencies of certain T cell sub-populations in female, but not male, offspring. Additionally, in the EAE model disease onset occurred earlier and was more severe in females. Our findings indicate that developmental exposure to this mixture had persistent immunological effects that differed by sex, and exacerbated responses in an experimental model of autoimmune encephalitis. These observations suggest that developmental exposure to complex mixtures of water contaminants, such as those derived from UOG operations, could contribute to immune dysregulation and disease later in life. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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3. Regulation of T Cell Motility In Vitro and In Vivo by LPA and LPA2.
- Author
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Knowlden, Sara A., Capece, Tara, Popovic, Milan, Chapman, Timothy J., Rezaee, Fariba, Kim, Minsoo, and Georas, Steve N.
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T cells ,CELL motility ,LYSOPHOSPHOLIPIDS ,AUTOTAXIN ,LYMPHOCYTES ,LYMPH nodes ,ENDOTHELIAL cells ,CELL migration - Abstract
Lysophosphatidic acid (LPA) and the LPA-generating enzyme autotaxin (ATX) have been implicated in lymphocyte trafficking and the regulation of lymphocyte entry into lymph nodes. High local concentrations of LPA are thought to be present in lymph node high endothelial venules, suggesting a direct influence of LPA on cell migration. However, little is known about the mechanism of action of LPA, and more work is needed to define the expression and function of the six known G protein-coupled receptors (LPA 1–6) in T cells. We studied the effects of 18∶1 and 16∶0 LPA on naïve CD4+ T cell migration and show that LPA induces CD4+ T cell chemorepulsion in a Transwell system, and also improves the quality of non-directed migration on ICAM-1 and CCL21 coated plates. Using intravital two-photon microscopy, lpa2−/− CD4+ T cells display a striking defect in early migratory behavior at HEVs and in lymph nodes. However, later homeostatic recirculation and LPA-directed migration in vitro were unaffected by loss of lpa2. Taken together, these data highlight a previously unsuspected and non-redundant role for LPA2 in intranodal T cell motility, and suggest that specific functions of LPA may be manipulated by targeting T cell LPA receptors. [ABSTRACT FROM AUTHOR]
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- 2014
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4. The Acute Environment, Rather than T Cell Subset Pre-Commitment, Regulates Expression of the Human T Cell Cytokine Amphiregulin.
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Yilin Qi, Operario, Darwin J., Georas, Steve N., and Mosmann, Tim R.
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T cells ,GENE expression ,AMPHIREGULIN ,PHENOTYPES ,LABORATORY mice - Abstract
Cytokine expression patterns of T cells can be regulated by pre-commitment to stable effector phenotypes, further modification of moderately stable phenotypes, and quantitative changes in cytokine production in response to acute signals. We showed previously that the epidermal growth factor family member Amphiregulin is expressed by T cell receptor-activated mouse CD4 T cells, particularly Th2 cells, and helps eliminate helminth infection. Here we report a detailed analysis of the regulation of Amphiregulin expression by human T cell subsets. Signaling through the T cell receptor induced Amphiregulin expression by most or all T cell subsets in human peripheral blood, including naive and memory CD4 and CD8 T cells, Th1 and Th2 in vitro T cell lines, and subsets of memory CD4 T cells expressing several different chemokine receptors and cytokines. In these different T cell types, Amphiregulin synthesis was inhibited by an antagonist of protein kinase A, a downstream component of the cAMP signaling pathway, and enhanced by ligands that increased cAMP or directly activated protein kinase A. Prostaglandin E2 and adenosine, natural ligands that stimulate adenylyl cyclase activity, also enhanced Amphiregulin synthesis while reducing synthesis of most other cytokines. Thus, in contrast to mouse T cells, Amphiregulin synthesis by human T cells is regulated more by acute signals than precommitment of T cells to a particular cytokine pattern. This may be appropriate for a cytokine more involved in repair than attack functions during most inflammatory responses. [ABSTRACT FROM AUTHOR]
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- 2012
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5. Resolving lung injury: a new role for Tregs in controlling the innate immune response.
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Pietropaoli, Anthony and Georas, Steve N.
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LUNG injuries , *IMMUNE response , *INFLAMMATION , *CRITICAL care medicine , *INTENSIVE care units , *LABORATORY mice , *PHYSIOLOGY , *ANIMALS , *IMMUNITY , *MICE , *T cells , *ACUTE diseases - Abstract
Inflammation-associated lung injury is a major cause of morbidity and mortality for patients in intensive care units. Although the cellular and molecular events that initiate lung inflammation are now well understood, the mechanisms that promote its resolution remain poorly defined. In this issue of the JCI, D'Alessio et al. show in a mouse model that recovery from acute lung injury is not simply a passive process, but involves Tregs in an active resolution program (see the related article beginning on page 2898). [ABSTRACT FROM AUTHOR]
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- 2009
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6. Enhanced Interferon-γ Gene Expression in T Cells and Reduced Ovalbumin-Dependent Lung Eosinophilia in Hypoxia-Inducible Factor-1-α-Deficient Mice.
- Author
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Guo, Jia, Lu, Wenju, Shimoda, Larissa A., Semenza, Gregg L., and Georas, Steve N.
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GENE expression ,TRANSCRIPTION factors ,INTERFERONS ,EOSINOPHILIA ,LUNG physiology ,HYPOXEMIA ,T cells ,LABORATORY mice ,DIAGNOSIS - Abstract
Background: There is growing evidence that hypoxia-inducible transcription factors are involved in the pathophysiology of asthma. Hypoxia-inducible factor-1α (HIF-1α) in particular controls the expression of many hypoxia regulated genes, but whether HIF-1α directly contributes to allergen-driven immune responses is not known. Methods: Partially HIF-1α-deficient mice (HIF-1α
+/– ) or wild-type littermate controls were used in all experiments. Spleen CD4+ T cells were stimulated with anti-CD3 plus anti-CD28 antibodies and cytokine secretion was measured in vitro. Mice were sensitized by intraperitoneal injection of ovalbumin (Ova) plus alum, and then challenged by intranasal Ova followed by bronchoalveolar lavage (BAL) and isolation of spleen cells. BAL cells were counted and the differential determined using cytospin, and splenocytes were incubated with Ova to measure recall cytokine production. Results: Interferon-γ secretion was significantly higher in anti-CD3 plus anti-CD28 stimulated CD4+ T cells obtained from HIF-1α+/– mice compared to wild-type controls. HIF-1α+/– mice were protected from lung eosinophilia 72 h after allergen challenge, in association with enhanced secretion of interferon-γ in recall responses of splenocytes. Conclusions: HIF-1α contributes to allergic immune responses and lung eosinophilia in a mouse model of asthma. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]- Published
- 2009
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7. Yin-Yang 1 regulates effector cytokine gene expression and TH2 immune responses.
- Author
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Guo, Jia, Lin, Xin, Williams, Marc A., Hamid, Qutayba, and Georas, Steve N.
- Subjects
CYTOKINES ,T cells ,GENE expression ,IMMUNE response - Abstract
Background: The transcription factor Yin-Yang 1 (YY-1) binds to the promoter regions of several T-cell cytokine genes, but the expression and contribution of this factor to cytokine gene expression and T-cell activation in vivo is not clear. Objective: We sought to better define the role of YY-1 in T-cell gene regulation and allergic immune responses. Methods: We studied cytokine gene expression in T lymphocytes isolated from wild-type mice and heterozygous littermates bearing 1 targeted yy-1 allele (yy-1
+/− mice). T cells were stimulated with anti-T-cell receptor (anti-TCR) plus CD28 antibodies or with peptide antigen plus antigen-presenting cells by using newly generated yy-1+/− TCR transgenic mice. We also studied ovalbumin-driven allergic immune responses in a mouse model of asthma and YY-1 expression in lung tissue from human asthmatic subjects. Results: CD4+ T cells from yy-1+/− mice secreted significantly less IL-4 and IFN-γ compared with wild-type littermates after TCR-dependent activation, whereas IL-2 production was not significantly affected. Both airway inflammation and recall splenocyte IL-4 production were inhibited in yy-1+/− mice, as was antigen-driven T-cell proliferation. YY-1 expression was higher in airway biopsy specimens from asthmatic compared with control subjects. Conclusion: These data indicate that YY-1 regulates T-cell cytokine gene expression and allergic immune responses in a gene dose-dependent manner. [Copyright &y& Elsevier]- Published
- 2008
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8. Ambient particulate matter directs nonclassic dendritic cell activation and a mixed TH1/TH2-like cytokine response by naive CD4+ T cells.
- Author
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Williams, Marc A., Porter, Michael, Horton, Maureen, Guo, Jia, Roman, Jessica, Williams, D'Ann, Breysse, Patrick, and Georas, Steve N.
- Subjects
DENDRITIC cells ,CYTOKINES ,CD4 antigen ,T cells - Abstract
Background: Dendritic cells (DCs) translate environmental cues into T-cell activating signals, and are centrally involved in allergic airway inflammation. Ambient particulate matter (APM) is ubiquitous and associated with allergic diseases, but it is unknown whether APM directly activates DCs. Objective: To study comprehensively the effects of APM on myeloid DC phenotype and function. Methods: Development of DC was modeled using human CD34
+ progenitor cells. APM was collected from ambient outdoor air in Baltimore city. We studied the effects of APM on DC activation in vitro, compared with LPS. Results: Ambient particulate matter enhanced DC expression of costimulatory receptors but suppressed the expression of both the endocytosis receptor CD206 and uptake of fluorescein isothiocyanate–conjugated dextran. The expression of the Toll-like pattern-recognition receptors Toll-like receptor 2 and Toll-like receptor 4 was also blunted. APM-exposed DCs secreted less IL-12 and IL-6 but exhibited increased secretion of IL-18 and IL-10 compared with LPS stimulation. A TH 2-like pattern of cytokine production was seen in cocultures of APM-stimulated DCs and alloreactive naive CD4+ T cells where the IL-13 to IFN-γ ratio was reversed. This contrasted with the TH 1 polarizing effects of LPS on DCs. Conclusion: We report for the first time that APM-exposed DCs direct a complex TH 1/TH 2-like pattern of T-cell activation by mechanisms that involve nonclassic activation of DCs. Clinical implications: Inhaled APM can act directly on DCs as a danger signal to direct a proallergic pattern of innate immune activation. [Copyright &y& Elsevier]- Published
- 2007
- Full Text
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