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1
Roey, Griet Van. "Modulating mucosal immune responses to HIV." Thesis, St George's, University of London, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589775.
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Development of a successful vaccine against HIV is likely to require the induction of strong and long-lasting humoral immune responses at the mucosal portals of virus entry. One approach to achieve this is the direct immunisation of mucosal sites. However, there is a need for potent and safe adjuvants that work at mucosal surfaces. A number of cytokines have recently been identified that specifically activate B-cells including BAFF, APRIL and TSLP. The hypothesis of this thesis is that these cytokines will act as adjuvants to boost antibody responses to mucosally delivered HIV antigen. Following immunisation of mice, serum and vaginal samples were tested for gp140-specific IgA and IgG responses. Splenocytes were assessed for T-cell proliferation and gp140-specific IgA and IgG antibody secreting cells. Cytokine production by T-cells after in vitro stimulation with CN54gp140 peptides was also assessed. TSLP, but not APRIL or BAFF, induced strong immune responses after nasal " immunisation, comparable to those seen with cholera toxin. Responses were still detected 4 months after the last boost, indicating a long lasting response. TSLP also induced T -cell proliferative responses to gp 140 after nasal immunisation and induced a T H2 type immune response but without induction of an allergic response. Due to cost limitations on the mass production of protein for use as an adjuvant, it was also tested whether TSLP could be delivered in the form of a plasmid DNA adjuvant. These studies demonstrated limited efficacy. In conclusion, the study demonstrated that B-cell activating cytokine TSLP, but not BAFF and APRIL can work as a mucosal adjuvant. It is notable that there was no significant development of allergic responses following administration of TSLP. This is 4 , the first time that TSLP has been demonstrated to have a positive effect as a mucosal adjuvant, and specifically promoting mucosal and systemic responses to HIV gp140.
2
Kannan, Yashaswini. "Functional Characterization Of Human IkappaBzeta In Modulating Inflammatory Responses." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1314564642.
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Lay, Abigail C. "Understanding and modulating insulin responses of the glomerular podocyte." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.684357.
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Podocytes are highly specialised epithelial cells, located on the urinary side of the glomerular filtration barrier. Disruptions to podocyte structure and function results in a disruption to the filtration process and proteinuria. Therefore, an understanding of factors that influence podocyte biology is desirable. Podocytes respond to insulin both in vitro and in vivo and the podocyte-specific knock-down of the insulin receptor results in a glomerular pathology with features characteristic of diabetic nephropathy. There is also evidence that podocyte insulin signalling is disrupted in models of insulin resistance and diabetes. The aim of this thesis was to investigate how both positive and negative modulators of insulin signalling specifically influence podocyte responses in vitro. Initial work was undertaken to characterise the responses of a recently developed mouse podocyte cell line. These cells express the insulin and insulin-like growth factor {IGF)-I receptors, and the phosphorylation of these proteins is evident following insulin stimulation. Downstream of receptor activation, increased phosphorylation of insulin receptor substrate (IRS) proteins and activation of phosphoinositide 3-kinase {PI3K)/Akt and MEK/ERK mitogen activated protein kinase (MAPK) cascades is observed . Furthermore, these cells activate glucose transport pathways following insulin stimulation. The effects of the anti-diabetic agent metformin and the selective chemical inhibition of protein tyrosine phosphatase 1B (PTP1B) were next examined, as potential enhancers of podocyte insulin signalling. Data herein demonstrates that these chemicals have direct effects on mouse podocytes in vitro and influence cellular glucose uptake. The modulation of podocyte signalling by diabetic factors, specifically the chronic exposure to high insulin, high glucose and inflammatory cytokines, was also investigated. Data reveals that the exposure of podocytes to a combination of these diabetic factors disrupts the activation of insulinstimulated signalling and glucose uptake. Individually, these factors exert their effects at different points within the signalling network. Quantitative peR arrays were also performed to identify changes at the mRNA level. Interestingly, the mRNA encoding the neurotransmitter Neuropeptide Y (NPY) was down regulated by 7-fold following cytokine exposure. Further investigation demonstrates that this peptide signals to both human and mouse podocytes in vitro stimulating the phosphorylation of Akt and ERK1/2, as well as influencing calcium signalling. Overall, work within this thesis demonstrates both the positive and negative modulation of podocyte insulin signalling in vitro and identifies a novel role for NPY in podocyte biology.
4
Salazar, F. "The role of indoleamine 2,3-dioxygenase in modulating allergic responses." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/33071/.
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Dendritic cells (DCs) are key players in the induction and re-elicitation of T helper (Th) 2 immune responses to allergens. Recent data by our group have shown that different C-type lectin receptors (CLRs) on DCs play a major role in allergen recognition and uptake. Particularly, mannose receptor (MR), through modulation of Toll-like receptor (TLR) 4 signalling pathway, can regulate indoleamine 2,3 dioxygenase (IDO) activity favouring Th2 responses. IDO is the rate limiting enzyme involved in tryptophan (TRP) catabolism and it is well known for its role in modulating immune responses through TRP depletion and generation of immune-regulatory metabolites known as kynurenines (KYN). Interestingly, another CLR named dendritic cell-specific intracellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) has been suggested to support Th1 responses; however, the mechanisms involved are unknown. Therefore, the main objective of this project was to evaluate the role of CLRs, with focus on MR and DC-SIGN, and TLRs in modulating the IDO pathway in order to understand their involvement in regulating Th2 immune responses. In addition, it was aimed to study how regulation of IDO levels could impact immune responses in order to understand the signalling pathways involved in this process. The data show that mannosylated allergens can down-regulate TLR4-induced IDO1 and IDO2 expressions as well as IDO activity in human DCs, most likely through binding to the MR. This correlates with data showing increased IDO activity in MRlow-DCs (generated by gene silencing) stimulated with mannan compared with control-DCs (CT-DCs). Conversely, DC-SIGN could exert a differential regulation on IDO levels depending on the antigen’s sugar moieties. Mannosylated ligands could up-regulate TLR4-induced IDO activity through DC-SIGN as evidence by a significant reduction in IDO activity in DC-SIGNlow-DCs upon stimulation with mannan compared with CT-DCs. In contrast, DC-SIGN-specific fucosylated ligands, such as Lewis-X (LeX), can down-regulate IDO activity in a TLR4-dependent manner. It was also found that allergens from diverse source can down-regulate IL-12p70 production by DC, which can further impact T helper cell polarization by reducing IFN-γ production by T cells in autologous co-cultures. Moreover, mannan was also shown to decrease CD86 expression in human DCs, which might impact the IDO pathway, as CD86 is one of the B7 family molecules involved in IDO induction. Furthermore, it was found that the LeX can potentially down-regulate IL-6 production by DCs. In addition, DCs stimulated with LeX and LPS induce lower levels of IFN-γ production by autologous T cells than DCs stimulated with LPS only. This effect was reversed in the presence of KYN, showing that the IDO pathway can regulates T helper cell polarization. TLR4 signalling and LPS exposure have been shown to play a pivotal role in Th2-mediated inflammation and asthma. In addition, it is known that CLRs can modulate TLR-induced responses in an allergy context. Therefore, we further study the role of the TLR signalling pathway in modulating IDO levels in human DCs. TLR4 engagement on human DCs was shown to induce high levels of both IDO isoforms. DCs primed with LPS induce much higher levels of IDO than single LPS controls, inducing a cellular re-programing. This was characterized by an induction of anti-inflammatory mediators such as IL-10 and the transcription factor aryl-hydrocarbon receptor (AhR); the last has been previously linked with the IDO pathway in mouse DCs. Intriguingly, TLR9 engagement with synthetic cytosine-phosphate guanosine (CpG) A motifs was able to down-regulate IDO and induce a pro-inflammatory phenotype in human DCs. Future studies should aim at evaluating their implications in immune responses under tolerance and during infection. Finally, the study was aimed at elucidating the intracellular molecules involved in IDO regulation in human DCs. The analysis was first focused on AhR, a ligand-dependent transcription factor that have been suggested to modulate IDO levels in mouse DCs. It was shown for the first time that TLR4 induction of IDO was dependent on AhR in human DCs. In addition, AhR gene expression as well as AhR activity were reduced in DCs stimulated with mannan and LPS compared with LPS only controls. This data suggest that MR can regulate IDO levels by interfering with AhR expression. Furthermore, it was shown that the NF-κB pathway is key in regulating IDO levels through CLRs and TLRs in human DCs. Particularly, RelB, a member of the non-canonical pathway, expression correlates with the levels of AhR, suggesting that a functional and/or physical association between them might be involved in regulating IDO levels in human DCs. Future studies should aim at elucidating such interactions. To sum up, this project has shown the pivotal role of CLRs and TLRs in modulating the IDO pathway in human DCs, which can affect DC phenotype and function and impact immune responses. In addition, we have gained some understanding into the molecular mechanisms of IDO modulation which might involve cooperation between different transcription factors such as AhR and RelB. These data give new insights into how glycosylated allergens can induce Th2 immune responses, which can pave the way to develop better therapeutic strategies to fight back allergy related diseases.
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Chute, Christopher. "Decoding Neural Circuits Modulating Behavioral Responses to Aversive Social Cues." Digital WPI, 2018. https://digitalcommons.wpi.edu/etd-dissertations/496.
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Understanding how the human brain functions on a molecular and cellular level is nearly impossible with current technology and ethical considerations. Utilizing the small nematode, Caenorhabditis elegans, and its innate behavioral responses to olfactory social cues, we can begin to unravel the mechanisms underlying social behavior. This is made possible given that innate behaviors are crucial for survival, and therefore hardwired into the genome of organisms. This allows for genetic-level analysis of neural circuitries driving behavior. Studying the neuronal mechanisms underlying C. elegans’ behavioral responses to social cues will not only assist in our overall understanding of how the brain perceives stimuli to enact a behavioral response at the cellular and molecular level, but also our understanding as to how the nervous system properly integrates information to enact social behavioral responses: mis-integration and social abnormalities are commonalities seen in many neuropsychiatric disorders, and these studies will provide fruitful insights into the defects observed in these disorders. Lastly, by comparing the perception of several different types of social chemicals, we can further our understanding of neural coding strategies for the various behaviors crucial for survival. Chapter One of this thesis orients the reader to social, innate behavior, and the usefulness of C. elegans as a tool for understanding behavioral coding. Chapter Two explores and establishes the required components of a socially aversive pheromone, providing insight into signaling evolution and co-option of biological machineries. Chapter Three examines how multiple, competing stimuli are integrated to modulate behavioral output, furthering our understanding of molecular and cellular integration and decision making within the nervous system. Chapter Four highlights the importance of predator pressure, and provides insights into circuit strategies of redundant and promiscuous networks of threat detection. Lastly, Chapter Five considers the implications of these findings as a whole, in the perspective of evolutionary strategies leading to neuronal coding of different behavioral outputs. Taken together, this dissertation aimed to fill the void in our understanding of social behavior neural circuitries, and how integration governed at the molecular and cellular level of the nervous system affects those behaviors.
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Suen, Victoria Melissa. "Investigating the role of defined microbes in modulating skin immune responses." Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/investigating-the-role-of-defined-microbes-in-modulating-skin-immune-responses(bb414aa0-66d9-4a4e-8f8b-56a9cc51b7e6).html.
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The skin represents the primary interface between the host and the external environment. It is home to an array of microorganisms that are crucial in maintaining homeostasis and controlling local immunity. Accumulating evidence suggests that skewing of microbial colonisation is critically linked to the development of different skin diseases such as atopic dermatitis (AD) and psoriasis. Among those S. aureus and C. simulans are of special interest for AD and psoriasis respectively, whereas L. crispatus appears to be relevant for healthy skin. However, little is known about how host-microbe interactions can trigger or regulate inflammatory processes in the skin. Dendritic cells (DCs) play a pivotal role in immunological responses and were therefore used in this study to explore the effect of key microbes on skin immunity. The aim of the project was to investigate the direct effects of defined microbes on different DC subsets and their indirect effects on adaptive immune responses. This study demonstrates that different DC subsets in skin exhibit unique immune responses to specific microbes. Langerhans cells were unresponsive to bacterial extracts whereas dermal DCs (DDCs) were more readily matured. Notably, CD141+ DDCs were the only subset to be activated by L. crispatus and produced a range of cytokines after bacterial stimulation. Next it was shown that DC priming with specific microbes, such as L. crispatus-primed CD141+ DDC-like DCs, could induce a distinct population of CD25+ FoxP3hi-expressing T cells, which was impaired in psoriasis patients. Despite phenotypic resemblance to T regulatory (Treg) cells, these cells failed to exhibit suppressive function. Functional specialisation of DC subsets could account for the compartmentalised host regulation of immunogenic or tolerogenic responses to skin microbes. Overall, cutaneous immune cells act in a coordinated manner with specific microbes to calibrate immune status with profound implications for homeostasis and skin disease.
7
Ebner, Friederike. "The role of microglia phenotypes in modulating CD4 + T cell responses." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2014. http://dx.doi.org/10.18452/16882.
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Die Invasion von Leukozyten in das zentrale Nervensystem (ZNS) ist ein wesentlicher Bestandteil bei der Pathogenese von Hirnverletzungen sowie akuten und chronischen Entzündungsvorgängen im Gehirn. Mikrogliazellen, die überwiegende Population immunkompetenter Zellen des ZNS, stellen die erste Verteidigungslinie im Hinblick auf Verletzungen und Erkrankungen des Gehirns dar. Im Rahmen vieler neurodegenerativer Erkrankungen wird die Zerstörung von Neuronen, aber auch die kollaterale Gewebsschädigung auf die Aktivierung der Mikrogliazellen zurückgeführt. Die vorliegende Arbeit beschreibt erstmalig einen regulatorischen Aktivierungszustand der Mikroglia (CD40dimCD86dimIL-10high), der zur Induktion regulatorischer Foxp3+ T-Zellen (Treg) führt. Die Stabilität und funktionelle Aktivität Mikroglia-induzierter Treg konnte sowohl in vitro als auch in vivo gezeigt werden. In vitro inhibierten sie die Proliferation antigen-spezifischer Effektorzellen, in vivo führte ein adoptiver Transfer der regulatorischen T-Zellen zur Abmilderung des Krankheitsverlaufes experimentell induzierter, autoimmuner Enzephalomyelitis (EAE). Mikrogliazellen unterstützten sowohl die Proliferation bereits ausgebildeter regulatorischer T-Zellen als auch deren Differenzierung aus naiven T-Zellen. Die Induktion regulatorischer T-Zellen durch Mikroglia war Major Histocompatibility Complex (MHC)-II-abhängig und antigenspezifisch. Für Untersuchungen zur in vivo Relevanz wurden MHC-II-chimäre Mäuse generiert und eine Läsion im entorhinalen Kortex gesetzt. Fehlte MHC-II in ZNS-residenten Zellen, wurden weniger regulatorische T-Zellen pro Leukozyt in die lädierten Hemispheren rekrutiert. Zusammenfassend demonstrieren diese Ergebnisse das Modulationspotential von Mikrogliazellen auf die CD4+ T-Zellantwort. Die Mikroglia-induzierte Differenzierung und Proliferation von Foxp3+ regulatorischen T-Zellen ist ein möglicher Mechanismus der Regulation von Entzündungsvorgängen im ZNS durch Mikrogliazellen.The invasion of leukocytes into the central nervous system (CNS) is a key event in the pathogenesis of CNS injury and acute or chronic inflammatory neurological diseases. However, regulatory mechanisms of local innate immune responses that limit CNS inflammation are only poorly understood. Microglia are the predominant innate immune cells of the brain and present the first line of defence in CNS injury or disease. In the context of neurodegenerative disease, microglia activation accounts for collateral tissue damage and neurodestruction. This thesis for the first time describes a regulatory microglia phenotype (MHCII+CD40dimCD86dimIL-10high) that induced a strong Foxp3+ regulatory T cell (Treg) response. Microglia-induced Treg cells were stable and functionally active in vitro by inhibiting antigen-specific proliferation of effector T cells and in vivo, by attenuating experimental autoimmune encephalomyelitis (EAE) disease course after adoptive transfer. The data also suggested that regulatory microglia can mediate both, proliferation of Foxp3+ Treg cells and de novo differentiation from naive CD4+ T cells. Microglia-mediated Treg induction was proven to be MHCII and antigen-dependent. Using entorhinal cortex lesion (ECL) as a brain injury mouse model, diminished Foxp3+ Treg cell recruitment per infiltrated leukocyte in chimeric mice lacking MHCII specifically in the CNS was demonstrated, indicating in vivo relevance of antigen presentation by brain resident cells. Taken together, these findings demonstrate that microglial cells can directly modulate CD4+ T cell responses by regulating molecule levels for efficient antigen presentation and levels of secreted cytokines and chemokines. Microglia-mediated differentiation and proliferation of Foxp3+ Treg cells can be one of the mechanisms how microglia contribute to local immune homeostasis and limit CNS inflammation.
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El-Yassir, Nada. "The role of different 5-HT receptor subtypes in modulating nociception in the rat." Thesis, University of Edinburgh, 1989. http://hdl.handle.net/1842/30179.
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Masri, S. Hajar. "The role of natural killer T cells in modulating antigen-specific immune responses." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497047.
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Huang, Huang. "The Role of CD39 in Modulating Effector Immune Responses in Inflammatory Bowel Disease." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17295870.
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Inflammatory bowel disease is associated with excessive inflammation of the bowel and intestinal tissues in genetically susceptible individuals. IBD can manifest in two major forms, ulcerative colitis and Crohn’s disease. T helper type 17 cells (Th17) are effector lymphocytes that have been linked to intestinal inflammation in both mice and humans. Effector Th17 cells and regulatory T cells (Treg) – a subset pivotal to immune-tolerance maintenance – derive from the same CD4 progenitors. Our investigation demonstrates that Th17 cells with suppressor activity (supTh17) can be generated upon induced regulatory T cell (iTreg) exposure to Th17 polarizing conditions. With immune suppressive function that differentiates it from Th17, suppressor Th17 (supTh17) expresses high levels of CD39, a membrane-bound protein that catalyzes conversion of pro-inflammatory extracellular nucleotides into nucleosides, such as adenosine. Interestingly, though supTh17 is detected in the peripheral circulation and lamina propria of healthy subjects, it is diminished in patients with Crohn’s disease. This finding has important clinical implications for the development of innovative therapeutic techniques for targeting inflammation in autoimmune diseases, such as IBD.
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Eshelman, Lee Renee. "Emotion regulation and PTSD: Modulating responses to threat-relevant stimuli among sexually victimized women." Miami University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=miami153130704215266.
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Campbell, Amanda Rose. "The Role of Cellular Crosstalk in Modulating Natural Killer Cell Responses to Immunotherapy for Cancer." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1459507631.
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Voulgaraki, Despoina. "The role of leukocyte membrane interactions in immune responses and as targets for modulating autoimmune disease." Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427652.
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SINGH, SHATRUPA. "AUGMENTATIVE ROLE OF PLANT GROWTH PROMOTING BACTERIA (PGPB) IN MODULATING RESPONSES AGAINST MITIGATION OF SALT STRESS IN TRIGONELLA FOENUM-GRAECUM." Thesis, DELHI TECHNOLOGICAL UNIVERSITY, 2021. http://dspace.dtu.ac.in:8080/jspui/handle/repository/18463.
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An experiment was conducted to evaluate the role of plant growth promoting bacteria (PGPB)
in mitigating salinity stress in Trigonella foenum graecum. Plants were subjected to three
different levels of salinity viz 0, 70 and 150 mM NaCl (electrical conductivity value 0.01, 7.67
and 15.50 mS cm-1
, respectively) using a completely randomized design experiment. PGPB
showed positive effects in mitigation of salinity stress in fenugreek plants and elevated various
growth responses viz. shoot and root length, shoot and root dry weight, leaf area and number
of leaves as compared to uninoculated plants. Microbial inoculation significantly enhanced the
physiological responses viz. photosynthetic rate, stomatal conductance, transpiration and
internal CO2 as compared to uninoculated plants. Biochemical aspects like carotenoids,
chlorophylls, nitrogen and protein content were also increased in the microbial inoculated
plants as compared to uninoculated plants. PGPB was very effective than in mitigating salinity
stress in fenugreek plant. The findings of this study revealed that PGPB inoculation can help
the plants to overcome the deleterious effects of salinity stress in fenugreek plants.
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Ebner, Friederike [Verfasser], H. D. [Akademischer Betreuer] Volk, B. [Akademischer Betreuer] Sawitzki, and A. [Akademischer Betreuer] Flügel. "The role of microglia phenotypes in modulating CD4 + T cell responses / Friederike Ebner. Gutachter: H.-D. Volk ; B. Sawitzki ; A. Flügel." Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2014. http://d-nb.info/1047168839/34.
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Oita, Radu Cristian. "The role of extracellular form of visfatin (eNAMPT) in modulating stress responses in cultured myocytes as a model of skeletal muscle ageing." Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/3086/.
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The understanding of the ageing process and of ageing-associated diseases represents a significant challenge for the scientific community, governments and society at large. I identified in skeletal muscle of murine models by microarray an increase in PPAR-β/δ expression during acute phase of hindlimb suspension (accelerated ageing), with a possible compensatory role, and an increase in expression levels of NR4A family of nuclear receptors in the skeletal muscle of caloric restricted rats (decelerated ageing). Adipose tissue has an endocrine role being actively involved in cross-talk with peripheral organs such as skeletal muscle. Visfatin is a recently discovered adipokine with pleiotropic functions. Unlike in other types of cells, in differentiated C2C12 myoblasts exogenous added visfatin (eNampt) did not act as an insulin-mimetic factor as shown by western blot and fluorescent assays. Visfatin treatment of differentiated C2C12 myotubes generated nevertheless an increase in the levels of reactive oxygen species as shown by fluorescent microscopy that was dependent on de novo transcription and translation of a new set of genes as revealed by RT-PCR. This increase in oxidative stress was independent of activation of the stress-activated protein kinases (MAPKs) such as ERK and p38, but dependent on NFkB activation as proved by western blot.
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Agbayani, Gerard Patrick. "The Roles of Selectin Ligands and Innate Immune Responses in Modulating Resistance to Intracellular Bacterial Infections in Murine Hosts with Altered Immunity." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/38046.
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Listeria monocytogenes (LM) and Salmonella enterica serovar Typhimurium (ST) are intracellular bacterial pathogens that cause invasive disease in immune-altered individuals, including the immunocompromised and pregnant women. The mechanisms that modulate innate immunity to intracellular infection, particularly during pregnancy, are not well-understood. Functional selectin ligands play critical roles in leukocyte recruitment during inflammation. Increased control of LM infection in functional selectin ligand-deficient (FtDKO) mice is associated with increased levels of circulating innate immune cells, despite defective leukocyte migration compared to WT mice. Adoptive transfer of WT and FtDKO bone marrow (BM) cells to irradiated WT and FtDKO recipients demonstrates that BM reconstitution and the increased neutrophil phenotype of FtDKO mice is independent of functional selectin ligand expression within the host environment. Thus, functional selectin ligand deficiency enhances inherent innate immune resistance to intracellular infection. We then examined the impact of pregnancy-associated immunological changes on maternal susceptibility to intracellular infections. ST infection in pregnant mice results in profound systemic infection, increased fetal loss and enhanced serum and placental expression of pro-inflammatory cytokines. Pregnant mice showed decreased ratios of pro-inflammatory Th17 cells relative to anti-inflammatory regulatory T cells (Tregs) when compared to non-pregnant mice during infection. Functional inactivation of Tregs in vivo restored control of infection and normal Th17-to-Treg ratios, and reduced fetal loss. These indicate that modulation of Th17 and Treg responses impacts maternal and fetal protection from ST infection. Lastly, we examined the roles of type I interferons (IFNs) in modulating innate immunity to intracellular infections during pregnancy. Type I IFN receptor deficiency (IFNAR-/-) enhances immunity to LM and ST in the non-pregnant state by limiting pathogen-induced leukocyte death. We show that pregnant IFNAR-/- mice infected with LM retain increased protection from infection relative to WT controls. In contrast, protection conferred by IFNAR deficiency against ST infection in the non-pregnant state is abrogated during pregnancy. Distinctive maternal responses to LM and ST are associated with differential regulation of leukocyte distribution and cytokine expression in maternal systemic and/or placental compartments. Taken together, modulation of key mechanisms involved in leukocyte recruitment, immune-regulation and cytokine signaling impact host susceptibility to intracellular infections.
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Jia, Zhongtao [Verfasser], Nicolaus von [Gutachter] Wirén, Klaus [Gutachter] Humbeck, and Malcolm [Gutachter] Bennett. "Exploiting natural variation to uncover genes modulating root foraging responses to low nitrogen in Arabidopsis thaliana / Zhongtao Jia ; Gutachter: Nicolaus Wirén, Klaus Humbeck, Malcolm Bennett." Halle (Saale) : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2019. http://d-nb.info/1220288144/34.
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Pradhan, Maitree [Verfasser], Ian T. [Gutachter] Baldwin, Ralf [Gutachter] Oelmüller, and Eva Holtgrewe [Gutachter] Stukenbrock. "Understanding the regulatory basis of defence signaling in plants : the role of Argonautes in modulating defense responses in Nicotiana attenuata / Maidree Pradhan ; Gutachter: Thomas Baldwin, Ralf Oelmüller, Eva Holtgrewe Stukenbrock." Jena : Friedrich-Schiller-Universität Jena, 2019. http://d-nb.info/1207272876/34.
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Durieux, M. E. "Grensincidenten Modulating the injury response /." Maastricht : Maastricht : Maastricht University ; University Library, Maastricht University [Host], 2001. http://arno.unimaas.nl/show.cgi?fid=12698.
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Masseoud, Feda N. "Estrogen-Induced Modulation of Innate and Adaptive Immune Function." Digital Archive @ GSU, 2009. http://digitalarchive.gsu.edu/biology_diss/62.
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Host defense against infection and disease relies on the reciprocal communication between the immune and neuroendocrine systems where sex hormones exert negative and positive feedback actions on immune functions. Indeed, sex hormones have been implicated in gender dimorphic immune response and in the potentiation of immune-related disorders. The female hormone estrogen plays a role as an immunomodulator and may exert immunosuppressive and immunostimulatory effects. Though many studies focus on estrogen’s role in immunity within the female reproductive tract and autoimmunity, the modulatory effects of estrogen on vaccine responses are largely unexplored. The insufficient efficacy of some vaccines in certain target populations, as for example the elderly population, is well recognized. Hormones fluctuate throughout an individual’s life, and females in particular undergo several necessary reproductive (pregnancy and menopause) and lifestyle (oral contraceptive use) changes which involve sex hormones. Vaccine efficacy might be influenced by endogenous estrogen levels or by exogenous estrogen administration. Therefore, in the pursuit of improved vaccine efficacy, it is necessary to consider such hormonal factors and their contribution to immune status. We have studied estrogen’s role in modulation of vaccine responses using a mouse ovariectomy model where exogenous estrogen delivery can be controlled. Our studies included two different types of vaccines, a bacterial toxoid formulation and a bacterial secreted protein formulation. Results from these studies indicate that estrogen enhances vaccine-specific antibody production by likely supporting a general TH2 pathway and also modulates expression of genes encoding molecules critical in innate immune signaling and required for development of proper adaptive immune responses and antigen clearance through antibody-mediated mechanisms. The level at which estrogen modulates antibody responses appears to be dependent on the route of vaccine administration. The enhancement of specific humoral responses may involve mechanisms involving TLR2 and antibody Fc receptor expression on macrophages, cells that link innate and adaptive immune responses. Advances in our understanding of the relationship between sex hormones and the immune system may provide new insights into the mechanisms by which hormones act and thus may be exploited to guide the design of future vaccine strategies.
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Ireland, H. Elyse. "Hsp72 modulation of inflammatory immune responses." Thesis, University of Chester, 2009. http://hdl.handle.net/10034/76354.
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The body initiates an immune response to danger signals. The Danger model of the immune system postulates that danger signals are produced by exogenous molecules from foreign invaders, such as bacteria, and endogenous molecules released from damaged or injured cells. The response involves antigen recognition leading to up-regulation of cytokines and cell surface markers, followed by the recruitment of antigen presenting cells and T-helper cells which determine how the immune system responds. Endogenous danger signals include Hsp72 and HMGB-1. This thesis describes the development of specific antibodies and ELISAs for use in the quantification and detection of intra-cellular Hsp72 from cell extracts, and released Hsp72 from cell cultures which enabled the confirmation of physiological levels of Hsp72 from model systems. The ability of endogenous Hsp72 to stimulate an immune response was demonstrated and this response was not solely due to LPS contamination of recombinant protein preparations. Hsp72 was able to augment the response to LPS. In the presence of another endogenous danger signal, HMGB-1, relative amounts of Hsp72 were shown to augment a pro-inflammatory response whilst being able to maintain an anti-inflammatory response demonstrating Hsp72 has the ability to modulate the immune response. Hsp72 was also shown to be able to stimulate an immune response by binding to cell surface receptors, which could be blocked by specific peptides corresponding to known receptors. These include some receptors not utilised by LPS. The proportion of these different danger signals has consequences for the progression and outcome of an immune response and this may well be modulated by imposition of a supplemental or future stress at different points. In the most severe case, this can lead to death through sepsis following trauma.
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Grove, A. "Modulation of beta2-adrenoceptor mediated responses." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599755.
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Holden, Keith. "Endothelial modulation of arterial vasoconstrictor responses." Thesis, University of Sunderland, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339530.
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Antonio, Nicole. "Modulating the inflammatory response towards cancer in Zebrafish." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.681725.
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Surgery is a key cancer therapy and is still the most effective method to treat human solid cancers, which have not yet metastasized. However, tissue damage is thought to trigger development of various cancers, provide a favourable niche for tumour reoccurrence, and facilitate the growth of pre-existing micro-metastases suggesting that surgery may have clinical consequences other than removal of the primary cancer. The zebrafish, Danio rerio, has emerged as an excellent model organism in which to study cancer cell biology. I have undertaken live imaging studies of neutrophil and macrophage interactions between wounds and pre-neoplastic RasG12V lesions in Zebrafish larvae, and show that the immune cells recruited to the wound are quickly drawn out from the wound by competing signals from pre-neoplastic cells. The increased exposure to innate immune cells leads to increased proliferation of preneoplastic cells, which I show is entirely dependent upon innate immune cells, and at least in part, due to PGE2 derived from the immune cells. I then extended this study into adult zebrafish expressing RasG12V, where melanoma development appears to be accelerated after chronic tissue wounding. While chronic infections, with accompanying inflammation, can lead to malignant changes over time, there is evidence that acute, febrile infections may be cancer preventative. I have investigated whether the introduction of a foreign immune stimulus - bacteria - in larvae can shift the polarisation of the innate immune system towards a defensive and cytotoxic response leading to inhibition of pre-neoplastic cell proliferation. This work was influenced by the century-old work of Dr. William Coley who successfully treated cancer patients by deliberately infecting patients and inducing a high fever.
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Wagner, Elizabeth Diane. "Modulation of genotoxic responses by environmental agents." Thesis, University of Surrey, 1999. http://epubs.surrey.ac.uk/843395/.
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A metabolite of a widely used pesticide, paraoxon, exerted a dramatic mutagenic synergistic effect in Salmonella typhimurium with a number of mammalian-activated or plant-activated aromatic amines and heterocyclic amines. The mutagenic synergy required an activated an aromatic amine, and was not attributable to the generation of new mutagenic products or to the modification of the stability of the activated aromatic amine products. Paraoxon modulated the genotoxic potency of dietaiy heterocyclic amines in human cells. The results of this study raise the concern of the environmental effects of organophosphorus ester insecticides. A clone of the Chinese hamster ovary cell line, AS52, was isolated, characterised and analysed under identical treatment conditions with the mutagens 2-acetoxy-acetylaminofluorene (2AAAF), ethyl methanesulphonate (EMS), and UV radiation. The genetic endpoints included acute DNA damage detected in the alkaline single cell gel electrophoresis (SCGE) assay, whole cell clastogenicity detected with laser beam flow cytometry and forward mutation at a target gene. There were statistically significant increases in DNA damage and forward mutation with all three mutagens. Statistically significant increases in chromosome damage were observed with 2AAAF and EMS but not with UV. A non-uniform distribution of DNA damage throughout the genome was indicated with the chemical mutagens in the SCGE assay. Another type of modulation in genotoxic response was investigated whereby numerous commercial soybean processing products and by-products were analysed for their antimutagenic and antigenotoxic activities. Antimutagenic activity was detected in a soybean processing by-product, soybean molasses and in an ethanol extract, fraction PCC. PCC protected mammalian cells against direct DNA damage, clastogenic damage and point mutation induced by 2AAAF. A fraction of PCC, PCC100 was an effective antimutagen in mammalian cells and in human lymphocytes. Analytical chemical studies identified the compounds responsible for the antimutagenic activity as the soyasaponins I, III and V.
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Easterfield, Alistair John. "Foetal modulation of maternal T lymphocyte responses." Thesis, St George's, University of London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325057.
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Ntonia, I. "Modulation of lateralised responses to primary affect." Thesis, City, University of London, 2016. http://openaccess.city.ac.uk/16213/.
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Do we use one cerebral hemisphere or both to process positive and negative emotions? Is it more physiologically economical for the brain to initiate responses to both types of primary affect from a unilateral locus, or does our readiness to react to emotional stimuli depend on the differential contribution of each hemisphere based on the approach or avoidance behaviours positive and negative affect elicit? This thesis is concerned with these questions that have so far remained unanswered even though they form a key part of emotional perception research. The behavioural literature has provided evidence for both unilaterally (right hemisphere) and bilaterally derived responses to different types of emotional stimuli, with the directionality of response patterns changing depending on stimulus type and task demands. The neuroimaging literature has addressed whether there is a functional need for the lateralised processing of basic emotional stimuli by mapping subcortical and cortical emotional attention networks, specific to different variants of only negative affect (i.e. fear, sadness). How this subcortically originating lateralisation manifests into observable behaviour however still remains to be established. This research therefore posits that hemispheric lateralisation may be a modulated process, and aims to explore how this modulation guides the directionality of our behavioural responses to primary affect. The thesis introduces a novel methodology that provides the first evidence of the modulation of emotional lateralisation by establishing a behavioural paradigm that can effectively investigate hemispheric lateralisation through measures of response efficiency. The thesis further investigates whether subcortically originating lateralisation may be inferred through its resulting behavioural response, by examining visual field asymmetries in responses to positive and negative affect through nasally and temporally viewed stimuli. Additionally, the thesis considers the modulating properties of contextual emotion-enhancing features of facial expressions such as direct vs. averted gaze and the presence of looming sounds on behavioural responses to negative affect, and also investigates whether individual variability in anxiety levels translates into lateralised responses to affect. Findings from the present thesis suggest that lateralisation is not a sustained, static phenomenon, but in fact a dynamic, modulated process that depends on subtle stimulus-contextual elements to subsequently translate into observable response.
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Yu, Cunjing. "Modulation of immune responses by UV irradiation." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/22813.
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Atopic dermatitis (AD) is a common, chronic relapsing inflammatory skin disease associated with cutaneous hyper-reactivity to environmental triggers that are innocuous to normal nonatopic individuals. AD affects 10% to 15% of children and 2% to 10% of adults in industrialized countries. There has been increasing interest in this disease triggered by its increasing prevalence in western societies and its contribution to the increasing health care costs. Yet, the underlying pathophysiologic and genetic mechanisms leading to the manifestation of AD are not clear. AD results from a complex interplay between environmental triggers, susceptibility genes including mutations in the keratinocyte protein filaggrin and altered immune responses resulting in allergic CD4+ T cell (Th2) immunity to epidermally encountered antigens. Regulatory T cells (Tregs) play an important role in controlling responsiveness to self-antigens and preventing autoimmune diseases, as well as in limiting inflammatory responses during inflammation and infection. Currently, studies investigating the number and function of Tregs in patients with AD have shown controversial results. It has been long established that symptoms of AD improve on exposure to sunlight. Narrowband UVB (NB-UVB) phototherapy is a common treatment modality for a variety of skin diseases. Considering the adverse effects for systemic treatment for severe adult AD, phototherapy, especially NB-UVB phototherapy may be a more practical long-term treatment. However, approximately 50% of patients over an 8-week treatment course do not improve after NB-UVB phototherapy. Therefore, it is important to identify characteristics of AD patients to determine whether they will respond to phototherapy and to avoid adverse effects for unresponsive patients. UVB exposure has also been associated with induction of Tregs in mice and increasing their numbers and/or functional capacity may offer benefit to patients with chronic AD. Active vitamin D (1,25(OH)2D3), one of the factors induced by UV-B radiation induces Tregs and is suggested to contribute to the suppressive effect of NB-UVB phototherapy. However, UV radiation could also have beneficial effects through other pathways known to affect immunoregulation. UVB exposure upregulates production of nitric oxide (NO) in the skin which also affects immune cell function. The protein filaggrin is broken down in differentiating keratinocytes to form the natural moisturizer of the skin. The gene encoding filaggrin (FLG) has been shown to be a major predisposing factor for AD. A key breakdown product is urocanic acid (UCA) which also acts as a natural sunscreen and undergoes trans-cis isomerisation on exposure to UV-B. Cis-UCA is known to modulate immune responses, however, the mechanisms of its action remain elusive. The production of all three compounds, vitamin D, cis-UCA and NO might all increase in the circulation of patients undergoing UVB phototherapy. While the immunomodulatory effect of Vitamin D is well described, cis-UCA and NO may also affect the behaviour of T lymphocytes systemically. Therefore, I investigated the effect of NO and cis-UCA on the phenotype and function of CD4+T cells and monocyte-derived dendritic cells (Mo-DCs) derived from peripheral blood mononuclear cells (PBMCs) from healthy volunteers. I also investigated the correlation between plasma concentration of 25(OH) vitamin D and nitrate, FLG genotype, circulating Tregs and clinical efficacy of NB-UVB phototherapy. My results showed that NO did not affect the phenotype of human mo-DCs and directly affected peripheral CD4+ T cells by inducing functional CD25+Foxp3+CD127-Tregs from CD4+CD25lo/- effector T cells. Moreover, NO increased expression of the of skin homing marker CLA on these Tregs, suggesting an increased ability of NO-induced Tregs to migrate to the skin. These NO-induced CD25+Foxp3+CD127-Tregs had immunosuppressive functions and inhibited autologous CD4+ T cell proliferation. Cytokines, at least IL-10, secreted by NO-treated CD4+ T cells were not sufficient for the suppressive function of NOinduced Foxp3+Tregs. The immune regulatory function of NO-induced Fopx3+Tregs required cell-cell contact and was mediated by membrane bound TGFβ and PD-1/PD-L1 but not CTLA-4. Results also showed that cis-UCA might have both pro- and anti-inflammatory effects. Cis- UCA significantly decreased the proportion of CD25hi Foxp3+ cells from activated CD4+ T cells. It also decreased the expression of vitamin D receptor in CD4+ T cells which may interfere with the immune regulatory function of vitamin D. These results suggested that there might be a fine balance between UV-induced anti-inflammatory molecules’ effect on CD4+ T cells. However, Cis-UCA also modulated CD4+ T cell directly by decreasing CD4+ T cell proliferation, decreasing phosphorylation of ERK after TCR activation, enhancing immune suppressive cytokines secretion, and inhibiting the percentage of CLA+CD4+T cells suggesting a decreased ability to migrate to the skin, . Cis-UCA also affected the phenotype and function of antigen presenting cells by decreasing the expression of HLA-DR, CD86 and CD40 on immature mo-DCs, which led to increased proportion of CD25+Foxp3+CD127- T cells when co-cultured with allogenic CD4+ T cells. Results generated from the clinical study in which all 29 patients got better after phototherapy suggested although circulating 25 (OH) vitamin D concentration was significantly increased after NB-UVB phototherapy, the change of circulating 25 (OH) vitamin D concentration did not correlate with disease improvement. This suggests that vitamin D is not the only pathway involved and that other molecules contribute to UVB-induced immune-regulation. The data also show that of the levels of circulating nitrate and the FLG genotype did not correlate with improvement / change with phototherapy. However, the expression of CD69 and CLA on circulating CD4+ T cells was decreased after treatment suggesting that UVB affected T cell activation and migration to the skin, and their importance in determining clinical responses requires further investigation. Taken together, the results from my study provide evidence that vitamin D is not the only molecule responsible for the beneficial effect of NB-UVB phototherapy. NO and cis-UCA may down-regulate immune responses by affecting human peripheral CD4+ T cells and mo- DCs phenotype and function. A further understanding of the effect of NO and cis-UCA on skin resident immune cells will provide more insights for narrowing NB-UVB phototherapy which will help to select patients that most likely to benefit from a mechanism-based treatment.
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Knight, Louise Alice. "Modulating sensitivity and response to DNA damaging cytotoxic drugs." Thesis, University of Portsmouth, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411554.
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劉展彤 and Chin-tung Lau. "Modulation of vascular response by equol." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B40721954.
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Lau, Chin-tung. "Modulation of vascular response by equol." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B40721954.
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Maue, Alexander C. "Modulation of bovine immune responses to genetic immunization /." Free to MU Campus, others may purchase, 2005. http://wwwlib.umi.com/cr/mo/fullcit?p3189940.
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Wållberg, Maja. "Modulation of immune responses in experimental autoimmune encephalomyelitis /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-335-3/.
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Longhi, Maria Paula. "Modulation of CD4+ T cell responses by CD59a." Thesis, Cardiff University, 2006. http://orca.cf.ac.uk/56047/.
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CD59 is a GPI-anchored protein found in membrane microdomains known as lipid rafts. It is a complement regulator protein, which blocks the formation of the membrane attack complex by inhibiting binding of C9 to the C5-8 complex. Human CD59 has also been described as a co-stimulator of T cell activation. The aim of this project was to analyze the role of CD59 on T cell activation in vivo. For this purpose, anti-viral CD4+ T cell responses were analyzed in mice deficient in the mouse analogue of CD59 CD59a. Infection with recombinant vaccinia virus (rVV) and influenza virus, resulted in stronger virus-specific CD4+ T cell responses in Cd59a -/- mice compared to WT mice. This effect, which indicates that CD59a downmodulates antigen-specific T cell activity, was found to be complement independent. Experiments were performed to investigate the effect of CD59 expression on human CD4+ T cells. Blocking CD59 increased proliferation of the cells in vitro indicating that CD59 might similarly downmodulate human CD4+ T cell activity. Using mouse T cells, mechanisms underlying the effect of CD59a on CD4+ T cell activity were investigated. Results of these studies indicated that downmodulation of T cell activity through CD59a requires engagement of CD59a with a ligand expressed on APCs. To assess the biological consequences of CD59a deficiency, the extent of immunopathology induced following infection with influenza virus was compared in WT and Cd59a-/- mice. Immunopathology was exacerbated in Cd59a-/- mice, correlating with increased numbers of neutrophils and CD4+ T cells in infected lungs. When complement was inhibited, lung-infiltrating neutrophils in Cd59a-/- mice were much reduced while numbers of infiltrating-CD4+ T cell remained unchanged. These results demonstrate that CD59a is more than a regulator of complement but can in fact, alter both the innate and adaptive immune responses using both complement dependent and independent mechanisms.
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Schulz, Kerstin Ingrid. "Modulation of Th1 and Th2 type immune responses." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390690.
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Saunders, Karin Anna-Lovisa. "Modulation of heterologous immune responses by gastrointestinal nematodes." Thesis, University of Strathclyde, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441881.
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Minter, Beverley E. "Modulation of inflammatory responses by mitochondrial targeted antioxidants." Thesis, University of Aberdeen, 2014. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=215108.
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Sepsis is a life threatening progression of a trauma or pathogen initiated systemic inflammatory response. Current treatment is supportive and depends mainly on antibiotics, fluids, and the careful administration of oxygen therapy. As sepsis progresses, it becomes a dysregulated inflammatory response, characterised by oxidative stress and excessive production of inflammatory cytokines, mitochondrial dysfunction and loss of antioxidant protection. Previous work on cells and animals has shown that novel antioxidants targeted to mitochondria may have a beneficial effect. To induce an inflammatory response and mitochondrial dysfunction, a human umbilical vein endothelial cell (HUVEC) in vitro mixed sepsis model with 0.2 μg/ml lipopolysaccharide (LPS) plus 20 μg/ml peptidoglycan (PepG) was used in the presence of a mitochondrially targeted vitamin E derivative, MitoVit E, and compared to the non-targeted vitamin E forms, Trolox and DL α-tocopherol acetate. Gene expression analysis was performed by quantitative polymerase chain reaction (qPCR) of the Toll-like receptor (TLR) 2 and 4 pathways from cells treated with the antioxidant +/- LPS/PepG for 4 h. Results showed that MitoVit E differentially regulated 11 genes compared to just four genes for the non-targeted forms of vitamin E. MitoVit E, Trolox and vitamin E were able to blunt IL-6 and IL-8 cytokine response in a dose-dependent manner. Inhibition of NFĸB gene and accessory protein expression was different for each antioxidant investigated along with effects on other inflammatory signalling proteins STAT 3 and MyD88. In addition, the antioxidants regulated radical production to similar extents, but had different effects on the reduced glutathione/oxidised glutathione, mitochondrial metabolic activity, mitochondrial membrane potential, oxygen consumption and mitochondrial number. In conclusion, MitoVit E showed encouraging effects in preventing dysregulation of the inflammatory response, maintaining mitochondrial membrane potential and radical production and normal cell function.
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Karlsson, Mattias. "Modulation of cellular innate immune responses by lactobacilli." Doctoral thesis, Örebro universitet, Institutionen för naturvetenskap och teknik, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-22138.
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Lactobacillus is a genus of lactic acid bacteria frequently used as healthpromoting probiotics. Using probiotics to treat or prevent infections is a novel experimental approach with vast impact on future therapy. Lactobacillus rhamnosus GR-1 is a probiotic investigated for its ability to reduce urogenital disease including urinary tract infections caused by pathogenic Escherichia coli. L. rhamnosus GR-1 has been shown to modulate immunity, thought to influence its probiotic effect. In this thesis, the aim was to study immunomodulation by L. rhamnosus GR-1 and other lactobacilli, with emphasis on elicited immune responses such as nuclear factor-kappaB (NF-κB) activation and cytokine release from human urothelial cells. Viable, heat-killed, and isolated released products from L. rhamnosus GR-1 augmented NF-κB activation in E. coli-challenged urothelial cells. Blocking of lipopolysaccharide binding to toll-like receptor 4 completely quelled this augmentation. Size-fractionation, urothelial cell challenge, and two-dimensional gel electrophoresis of L. rhamnosus GR-1 released products presented several candidate proteins with NF-κB modulatory actions including chaperonin GroEL, elongation factur Tu, and a protein from the NLP/P60 protein family. While tumor necrosis factor was correspondingly augmented by L. rhamnosus GR-1, the release of two other cytokines, interleukin (IL)-6 and CXCL8, was reduced. Similar effects were observed in macrophage-like cells stimulated with L. rhamnosus GR-1. Many immunomodulatory effects of lactobacilli are believed to be species and strain dependent. Therefore, twelve Lactobacillus strains were used to screen for their effects on CXCL8 release from urothelial cells. A majority of these strains were able to influence CXCL8 release from the cells. Phylogenetic analysis revealed close evolutionary linkage between lactobacilli with similar actions on CXCL8. Increased knowledge on probiotic bacterial products and the mechanism(s) of action could lead to improved future treatments for infections.
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Moore, Anthony Norman. "Selenium modulation of gut epithelial cell stress responses." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3679.
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Selenium (Se) is an essential micronutrient necessary for human health. In humans, Se de ciency has been associated with in ammatory bowel disease (IBD) and increased risk of certain cancers, including colorectal cancer. Se has well established antioxidant and anti-in ammatory properties which are medi- ated, in part, though the actions of the selenoproteins, in which Se is present in the form of the amino acid selenocysteine (Sec). The cells of the gastrointestinal tract are exposed to stresses from pro-oxidative and hypoxic conditions, which have been suggested to be involved in the pathogenesis and pathology of IBD. Further characteristics of IBD are inappropriate immune responses of the gut epithelial cells to the gut microbiota. Thus, to help explain the roles of Se in IBD, it is important to understand the modulatory e ects of Se on the cell innate immune responses following challenge of intestinal epithelial cells with pathogen-associated molecular patterns (PAMPs), as well as oxidative and hypoxic stresses. The present work aimed to assess the roles of Se and the selenoproteins, SelH and TR1, in the responses of Caco-2 cell, modelling the gut epithelium, to hypoxia and infection, the latter replicated by challenge with S. typhimurium agellin. To investigate the responses of gut cells to low Se and PAMPs, undi erentiated Caco-2 cells with either supplemented with Se (40 nM selenite) or depleted of Se for 72 h before challenging with agellin (F) (500 ng/mL). The gene expression of the pro-in ammatory cytokines IL-8 and TNF- were measured in addition to the genes encoding the antimicrobial peptides (AMPs) hBD1 and hBD2. Data showed that Se depletion signi cantly a ected hBD1 expression (0.88-fold increase, P < 0.05), but that Se depletion plus F signi cantly increased the induced expression of all genes (IL-8: 1.68-fold, P < 0.001; TNF- : 0.71-fold, P < 0.001; hBD2: 1.74-fold, P < 0.001) compared with the Se supplemented cells. F and Se depletion were also associated with a signi cant increase in expression of TR1 (F: 1.68-fold, P < 0.001; Se depletion: 0.33-fold, P < 0.01) and GPX2 (F: 3-fold, P < 0.001; Se depletion: 11-fold, P < 0.001), but a signi cant decrease due to Se depletion in SelH (62 %, P < 0.001) and GPX1 (47 %, P < 0.001). The selenoprotein TR1 is an antioxidant enzyme and the primary regulator of the thioredoxin system (TXN), which has previously been shown to regulate immune responses. Knockdown of TR1 expression resulted in the reduced agellin-induced expression of IL-8 (40 %, P < 0.001), TNF-a (45 %, P < 0.01), hBD1 (40 %, P < 0.01) and hBD2 (45 %, P < 0.001). These data suggested that Se, through TR1, is involved in regulating the expression of agellin-induced immune e ectors. The selenoprotein SelH has also been suggested to have antioxidant functions. Knockdown of SelH was associated with the increased expression of the oxidative stress-associated genes NQO1 (0.41-fold, P < 0.001), and HMOX1 (1.78-fold, P < 0.001), supporting a role for SelH in the expression of oxidative stress-associated genes. The role of Se, through SelH and oxidative stress, in regulating the gut responses to agellin, has been discussed. The Caco-2 cell model is more representative of intestinal epithelial cells in vivo, when the cells are di erentiated and placed in a gaseous environment re ecting the oxygen gradient of the gut. Thus the F challenge experiments using di erentiated Caco-2 cells were repeated using a dualoxic environment. Interestingly, no potentiation of gene expression relating to the pro-in ammatory agents IL-8 and TNF- , and the defensins hBD1 and hBD2 was observed. These data suggested that the dualoxic environment completely diminished the e ects of Se depletion on the expression of immune e ectors IL-8, TNF- , hBD2 and hBD1, following agellin challenge. These data suggested the e ects of Se in more physiologically relevant intestinal epithelial cell models, more representative of the in vivo state, are required.
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Clutton, Genevieve Tyndale. "HIV-specific interleukin-10 responses and immune modulation." Thesis, University of Oxford, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589623.
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Interleukin-l0 (IL-10) helps to limit the duration of potentially harmful inflammatory responses but has also been implicated in the persistence of a number of chronic viral infections. This thesis aimed to investigate the phenotype and function of mv -specific IL-l0-producing cells in chronic HIV-I infection, and the effect of IL-10 blockade on responses to candidate HIV -I vaccines. A cytokine capture assay was used to determine the HIV -specific cellular sources of IL- 10 in PBMC from 55 chronically infected individuals. A rare subset of CD8+ T cells was found to be the major HIV -I Gag-specific IL-10-producing population; these cells were restricted to ART-naive individuals and did not express the regulatory T cell markers CD25 or FoxP3 but could co-express IFN-y. A proportion of the population (median 48% and 9% respectively) expressed the P7 chain of the gut-homing integrin a4p7 and the chemokine receptor CXCR3, which mediates lymphocyte migration to sites of inflammation. Experimental depletion of Gag-specific IL-10+ CD8+ T cells did not affect T cell activation, or the production of cytokines such as IL-2 or IFN-y during short-term culture. However, depletion was associated with a significant increase in CD38 expression on CDI4+ monocytes, a trend towards increased HLA-DR expression on the same cells, and a significant increase in the concentration of the pro-inflammatory cytokine IL-6 in culture supernatants. There was also a significant increase in the number of HIV-infected (p24 antigen+) CD4+ T cells in cultures depleted of Gag- specific IL-10+ CD8+ T cells after 3 days, indicating that this population may contribute to control of viral replication. In order to determine the effect of IL-10 blockade on vaccine immunogenicity, IL-10R blocking antibody was administered to BALB/c mice prior to immunisation with two mV-I candidate vaccines, HIVA and HIVconsv. IL-10R blockade resulted in a trend towards increased IFN-y production by CD8+ T cells in response to the dominant H (Env) and P (Pol) epitopes of HIV A, and a significant increase in IFN-y ELISPOT responses to the subdominant Gl (Gag) epitope of HIV consv in vitro. Collectively, these data suggest that IL-10 producing cell populations may play critical but different roles in chronic infection and vaccination. Further research into how the timing of IL-10 responses affects disease outcome may allow IL-IO blockade to be explored as a therapeutic strategy in humans
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Wiater, Ezra M. "Modulation of cellular responses to activins and BMPs /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3112876.
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Floy, Brad Wayne. "Modulation of hamstrings reflexive responses during human gait." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/2871.
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In humans, it is thought that both central commands and peripheral feedback from sensory receptors contribute to the control of locomotion. An important problem that exists in human locomotion research is the interactions and balance between the individual contributions of the central (CNS) and peripheral (PNS) nervous systems to the control of muscles during movement are not fully understood. Applying external perturbations such as stretches, tendon taps, and electrical stimulation to the neuromuscular system during walking can help us learn more about how the response to afferent information is modulated during locomotion. To date, most of the research looking at modulation of the response during walking has investigated the soleus and quadriceps muscles. Very little research has focused on the hamstring muscles, which are important during walking, particularly during late swing. One reason for this is that it is difficult to detect H-reflexes in hamstrings following electrical stimulation of the sciatic nerve. The purpose of this study was to demonstrate a new sciatic nerve stimulation technique and use it to study the modulation of the response to afferent feedback during walking.
This study consisted of two parts: 1) Establish the presence of an afferent mediated response (H-reflex) during prone lying in hamstrings muscles, and 2) Investigate the modulation of this afferent feedback during walking. Subjects underwent single and double pulse stimulations to the sciatic nerve during prone lying, followed by electrical stimulation at 12 different phases of the gait cycle. For each phase, stimulus response curves were created in which maximal direct (M-wave) and afferent mediated responses (H-reflex) could be determined. Maximal H-reflex (Hmax) was normalized to maximal M-wave (Mmax) to create an H:M ratio that was used to compare modulation of the responses between phases and subjects. Electrical stimulation of the sciatic nerve elicited detectable H-reflexes in biceps femoris during prone lying and walking. The modulation of the response to afferent feedback is not the same for all phases of the gait cycle, particularly in late swing when it has a higher amplitude than the rest of the gait cycle. This modulation was not simply related to background EMG as would be expected during isometric contractions. Thus, there must be both central and peripheral influences on the response. Understanding the control of human locomotion is important for developing rehabilitation programs for patients with lesions of the central nervous system such as stroke or spinal cord injury.
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Wong, Choong Hin. "Wideband adaptive full response multilevel transceivers and equalizers." Thesis, University of Southampton, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310547.
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D'Arcy, Richard. "Macromolecular engineering for modulating the response of oxidation-sensitive polymers." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/macromolecular-engineering-for-modulating-the-response-of-oxidationsensitive-polymers(cb5f7eb6-b29e-4453-9c40-1d24b1b838f3).html.
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In this thesis the primary focus is on polysulfides, a class of oxidation-responsive polymers with potential biomedical applications as 1) polymeric anti-inflammatory/anti-oxidant agents and/or 2) drug delivery vehicles, specifically for inflammation and cancer. Within the Tirelli lab, polysulfides for inflammation targeting drug delivery are a key area of research and as such a comprehensive review of this topic is covered in Chapter 1. Polysulfides are able to target inflammation (and cancer) due to their inherent ability to react with reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) and hypochlorite (ClO-) which are markedly upregulated in inflamed and cancerous milieu; in Chapter 2 we demonstrate the different effects of these two oxidants on poly(propylene sulfide) (PPS) nanoparticles. Using diffusion-ordered NMR spectroscopy (DOSY), both size and spatial characteristics of the oxidation products were probed; specifically, the size of the oxidation products and the spatial location of Pluronic i.e. physically entrapped within the polysulfide core or ‘free’ Pluronic micelles. We additionally showed that these nanoparticles displayed a protective effect on both L929 fibroblasts and J774.2 macrophages when challenged with ClO-. In Chapter 3, micellar PEG-PPS composed of linear- (2-arm) or star-(4, 6 and 8 arm)shaped polymers were synthesised; we found micelles formed of the linear PEG-PPS reacted with H2O2 at a quicker rate than the star PEG-PPS, however, the critical micelle concentration of the stars was significantly lower indicating a marked increase in stability to dilution. Chapter 5 aimed to assess new monomer ethylene sulfide (ES), which was copolymerised with propylene sulfide (PS) and end-capped with PEG vinyl sulfone; the resulting PEG-P(PS-ES) copolymers were found to have a gradient composition due to the greater reactivity of ES. The rate of oxidation with the PEG-P(PS-ES) micelles (1:1 monomer composition) was ~2x faster with respect to PEG-PPS. The effect of primary structure on oxidation and gelation was evaluated using copolymers with various ES/PS gradients; there was little effect on oxidation kinetics, however, high ES gradients displayed significantly lower gel points; we ascribe this to the higher ES-ES association in polymers with longer ES sequences. Chapter 4 investigated the Mitsunobu reaction as a means to functionalize PEG-OH with a variety of commonly used (bio)conjugation groups (thiol, maleimide, azide and amine). This project arose when synthesising PEG-thioacetate as a potential macroinitiator for the polymerisation of PS/ES. Currently, the Mitsunobu reaction is scarcely used for the functionalization of PEG-OH but here we demonstrate its benefits over other commonly used functionalization methods; namely, it being a quantitative and high-yielding one-pot synthesis reaction.
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Gardner, Leanne M. (Leanne Margaret) 1977. "Modulation of the allergen-specific Tcell response." Monash University, Dept. of Pathology and Immunology, 2003. http://arrow.monash.edu.au/hdl/1959.1/5817.
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Pringle, Kerry Louise. "Modulation of the inflammatory response by antioxidants." Thesis, University of Southampton, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295920.
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Muller, Michael John. "Modulation of the response to cutaneous injury /." [St. Lucia, Qld.], 2000. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16146.pdf.
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Grainger, John Robert. "Immune modulation by parasitic nematodes." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/3809.
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Almost 2 billion people world-wide are infected with parasitic helminths. These complex multicellular eukaryotic organisms are capable of establishing long-term infections even in the face of an intact immune response. Typically, in these settings regulatory components of the immune response, such as Foxp3+ T regulatory cells (Tregs), become dominant, limiting protective effector responses towards the parasite. Helminths are thought to have evolved mechanisms, including release of immunomodulatory molecules termed excretory-secretory products (ES), to sway the balance between the regulatory and effector arms of the immune response to favour their persistence. In this thesis both the development of a protective immune response toward, and the potential manipulation of the immune response by, the rodent gastrointestinal nematode Heligmosomoides polygyrus have been studied. Firstly, the effects of H. polygyrus ES (HES) on bone-marrow derived dendritic cells (DCs) were analysed. Although HES did not alter the phenotype of the DC it was found to be able to suppress the ability of the DC to respond to inflammatory stimuli. This activity was lost when HES was heat-inactivated (hiHES). After adoptive transfer, HES-pulsed DCs were able to induce a HESspecific T helper (Th)2-type response even if co-treated with an inflammatory stimulus. Th2-type responses are protective against H. polygyrus infection. Surprisingly, the ability of HES to generate a Th2-response in a co-treatment situation was not related to its anti-inflammatory properties; DCs co-treated with hiHES and an inflammatory stimulus were able to drive an equivalent Th2-response to HES in this situation. Next, making use of mouse strains with different susceptibility phenotypes to primary H. polygyrus infection, potential mechanisms of resistance were characterised. Development of granulomas in the gut wall were found to be associated with reduced worm burdens. Furthermore, in highly susceptible C57BL/6 mice, production of IL-23 was shown to be counter-regulatory to this process, as mice on the same background but deficient in this cytokine have increased numbers of granulomas and dramatically enhanced resistance. Susceptibility to H. polygyrus was also considered at the level of epigenetic regulation. A protein that binds specifically to methylated DNA, methyl-CpG binding domain protein (MBD)2, was found to affect the proportion of Foxp3+ Tregs within the CD4+ T cell population in vivo. Additionally, in vitro induction of Foxp3 in response to TGF-β was enhanced in MBD2-/- CD4+ T cells. MBD2-/- mice had a trend towards increased worm burdens when infected with H. polygyrus, suggesting that the difference in proportion of Tregs may limit generation of an effector response. Finally, the ability of HES to directly affect the regulatory arm of the immune response was focussed upon. It was found that HES was able to induce Foxp3 expression in naïve peripheral T cells, and that this was mediated by stimulation of the TGF-β pathway. The TGF-β mimic was of parasite origin as a pan-vertebrate TGF-β antibody was unable to block its effects but sera from H. polygyrus infected animals was competent to do this. Activity of this type was not limited to HES as ES from the ovine helminth Haemonchus contortus was found to have the same property. These data imply that some helminth parasites have evolved mechanisms to support generation of Foxp3+ Tregs, thus favouring the regulatory arm of the immune response and hence their own persistence.
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Liwski, Robert Stefan. "Modulation of T cell-mediated responses by Nippostrongylus brasiliensis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0020/NQ49276.pdf.
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