Dissertations / Theses on the topic 'Immune'
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1
Vauleon, Elodie. "Implications des gènes immuns et des cellules immunes dans le glioblastome." Thesis, Rennes 1, 2013. http://www.theses.fr/2013REN1B005/document.
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Introduction : Le glioblastome (GBM) est la tumeur cérébrale primitive la plus fréquente et la plus grave de l’adulte. Des études épidémiologiques ont mis en évidence que les antécédents d’allergie sont un facteur protecteur, soulignant le possible impact de l’immunité sur le GBM. Plusieurs études transcriptomiques ont également mis en évidence des signatures immunes plus ou moins associées à la survie. Matériel et méthodes : Pour clarifier ce lien et déterminer quels gènes immuns étaient les plus impliqués dans le GBM, nous avons étudié l’expression de 791 gènes immuns dans des échantillons de GBM et de cerveaux normaux. Les interactions entre les gènes immuns ont été étudiées par une analyse de co-expression. Nous avons ensuite recherché une association entre les gènes immuns et la survie selon 3 méthodes statistiques, avant d’établir un modèle de risque mathématique validé sur plusieurs jeux de données. Enfin, nous avons étudié les cellules immunes infiltrantes sur des échantillons de gliomes dont 73 GBM par cytométrie de flux. Résultats : Un profil d’expression génique différent significativement entre le cerveau normal et le GBM a été établi de manière robuste, mais pas au sein des GBM. L’analyse de co-expression a mis en évidence 6 modules dont 5 sont enrichis en gènes ayant un lien avec la survie. Cent huit gènes immuns ont une association significative avec la survie et un prédicteur de risque à 6 gènes immuns a permis de distinguer deux groupes de patients en fonction de leur survie, y compris chez les patients dont la tumeur a un promoteur MGMT méthylé et dans le sous-groupe de GBM proneuraux. Enfin, nous avons mis en évidence, dans tous les échantillons de GBM analysés, une infiltration leucocytaire par des cellules macrophagiques/microgliales et parfois par des cellules lymphocytaires ou granulocytaires. L’infiltration de lymphocytes uniquement est associée significativement avec la survie dans notre cohorte. Conclusion : Des gènes, impliqués dans diverses fonctions immunes, sont différentiellement exprimés entre le cerveau normal et le GBM et au sein des GBM. Un prédicteur à 6 gènes robuste a été établi, il sépare les patients en 2 groupes bas et haut risque y compris ceux ayant un bon pronostic. Nous avons enfin mis en évidence dans une série de GBM une infiltration de cellules immunes, dont une infiltration lymphocytaire associée positivement à la survieBackground: Glioblastoma is the most common and lethal primary brain tumor in adults. Epidemiological studies have revealed that a history of allergies is a protective factor, thereby underlining the likely impact of the immune system on GBM. A number of transcriptomic studies have also identified immune signatures more or less associated with patient survival. Methods: In order to clarify and identify which immune-associated (IA) genes were the most involved in GBM, we studied the expression of 791 immune genes in GBM and normal brains samples. Interactions between IA genes were studied through an analysis of co-expression network. We then searched for a link between IA genes and patient survival according to 3 statistical methods, before defining a mathematical risk model based on different data sets. Finally, we studied the infiltrative immune population of 73 GBM by cytometry. Results: A significantly different profile of IA genes expression between healthy brains and GBM was consistently defined, but not among GBM. The analysis of co-expression network revealed 6 modules, 5 of which were enriched by genes associated with patient survival. 108 IA genes have a significant association with patient survival and the 6-IA gene risk predictor allowed us to distinguish two groups of patients according to their survival, including patients whose tumor had a methylated MGMT gene promoter and in the subset of proneural GBM. Finally, in every analyzed GBM sample, we have shown that there was a leukocyte infiltration by macrophages/microglial cells and sometimes by lymphocytes or granulocytes. Only the lymphocytes infiltration was significantly associated with the survival in our group of patients. Conclusion: IA genes that are involved in various immune functions are expressed differentially between healthy brains and GBM and amongst GBM. A robust 6-IA gene risk predictor was defined: it divides patients into two low and high risk groups, including those who have a good prognosis. Finally, we revealed an infiltration of immune cells in a series of GBM, only the lymphocytic infiltration was positively associated with patient survival
2
Nerurkar, Louis. "Neuro-immune responses to distal immune stimulus." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8529/.
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Depression is a major disease burden worldwide and, despite its prevalence and socioeconomic costs, around 30% of patients do not respond to currently available treatments. Inflammation is increasingly associated with, not only depressive illness but also resistance to existing therapies. This highlights the need for investigation of the mechanisms of neuro-inflammation, particularly in the context of peripheral inflammatory stimuli. Specifically, the chemokine molecular family is increasingly associated with human depressive illness, and neuro-inflammation and behavioural change in rodent models, making this an attractive molecular family for study. This thesis describes research aimed at investigating the association of these molecules with human depression and analysis of their role in an animal model of peripherally stimulated neuro-inflammation, the Aldara model of psoriasis-like inflammation. Systematic review and meta-analysis of the human biomarker literature using a random effects, inverse variance model revealed that a number of chemokines (CCL2, CCL3, CCL4, CCL11, CXCL4, CXCL7, CXCL8) are significantly associated with depressive illness in a human population. However this work revealed that there are a number of limitations of the human literature primarily associated with the methodological challenges of studies in human populations and confounding factors. Alongside this work, the Aldara model, which utilises the toll-like receptor 7 (TLR7) ligand imiquimod (IMQ), was investigated as a tool for studying neuroinflammation. Initial time-course investigation revealed that significant chemokine and cytokine transcriptional alterations occur within four hours at the local site of cutaneous treatment, the peripheral tissues and the brain. In addition, protein quantification in the brain confirmed that many of these transcriptional responses are translated to protein. Interestingly, it was shown that the brain response was temporally distinct from that of the peripheral tissues, and that in general brain responses were induced slightly more slowly and persisted for a longer period of time than those in the periphery. Investigation of Iba1+ (microglia/monocytes), GFAP+ (astrocytes) and CD3+ (T-cells) cells within the brain revealed significant changes in the microglial and T-cell populations, which were consistent with microgliosis and T-cell recruitment to the brain parenchyma. Changes in astrocyte populations were more equivocal although there was evidence of astrogliosis. Mechanistic investigations into responses to the Aldara model in inflammatory chemokine receptor (iCCR) KO mice did not reveal significant alterations in chemokine and cytokine transcription or in microglial responses to cutaneous Aldara treatment in the absence of the iCCRs (CCR1, CCR2, CCR3 and CCR5), but there did appear to be evidence of reduced CD3+ T-cell recruitment. In contrast, investigations in type I interferon receptor (IFNAR) KO mice identified a clear role for type I IFN signalling through IFNAR in the induction of chemokine and cytokine gene expression in the brain, and associated changes in Iba1+ microglial and CD3+ T-cell populations in response to cutaneous Aldara treatment. Mass spectrometric analysis of IMQ, the main active ingredient of Aldara, revealed that within four hours it enters both the circulation and the brain. The finding of IMQ within the brain parenchyma suggests that, while it is not an appropriate tool for studying peripheral-central immune crosstalk, it is a useful non-invasive model of TLR7 mediated neuroinflammation. These data provide compelling evidence of a role for chemokines in human depression and in neuro-inflammation, although the precise actions of this family of molecules remain unclear. In addition, building on previous work, the Aldara model appears to be a suitable tool for the study of neuro-inflammation, particularly interferon-driven immune responses, but is less appropriate for studying peripherally driven CNS immune reactions. Further work into the specific role of chemokines and associated cellular populations will hopefully provide additional insight into how CNS immune reactions are co-ordinated.
3
Johansson, Susanne. "Compartmentmentalized immuno-sequencing (cI-Seq) : identification of immune complex interactions." Thesis, KTH, Genteknologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-196872.
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Today, a lot of proteomic research is aimed at discovering disease specific proteins. This requires theavailability of high-throughput, ultra-sensitive protein detection methods. Compartmentalized immunosequencing(cI-Seq) is a proximity-independent immuno-polymerase chain reaction (IPCR) based proteindetection method. Antigen recognition in cI-Seq is mediated by antibody pairs in which one of theantibodies is conjugated to a DNA-probe. The affinity recognition events occur in emulsion droplets inwhich the DNA-probes will be amplified through emulsion PCR (emPCR) and thereafter analyzed usingMassively Parallel Sequencing (MPS). The amplifiable nature of the DNA-probes improves the sensitivityof the detection, while the use of emulsion droplets and MPS increases the multiplex capacity andthroughput. Ultimately, cI-Seq enables analysis and detection even of lowly abundant proteins therebyincreasing the probability of discovering novel disease specific proteins. In this project, conjugation of DNA probes to antibodies was performed through two different approaches;Covalent Conjugation and Conjugation using Biotin and NeutrAvidin. Both of these approaches showedadvantageous and disadvantageous features. However, neither of them succeeded in producing stableconjugates in an efficient and reproducible manner. After conjugation, the DNA-conjugated antibodieswere used in immune complex formation. However, the immune complexes either failed to form or wereformed in an inefficient manner.
4
Protheroe, Rachel Elizabeth. "Investigation of immune regulation in human alloreactive immune responses." Thesis, University of Bristol, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.520287.
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Rosa, Gustavo Luis Teixeira Lopes. "Studies of MHV-68 immune evasion and immune control." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611892.
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McIntosh, Alistair James. "The role of adipose tissue immune cells in immune responses." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8113/.
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Recent evidence indicates that immune cells within adipose tissues can drive the formation of ectopic lymphoid structures, known as Fat Associated Lymphoid Clusters (FALC). FALC support B-cell antibody production in response to infection and inflammation. This investigation explores the immune cell composition and role of different adipose tissues both in steady state and during immune responses in mice. Firstly, a detailed analysis of the immune cell composition of peritoneal adipose tissues was performed. To investigate the function and migratory properties of these tissue-resident cells, cytokine and chemokine receptor expression was then assessed. How immune cells in adipose tissues responded to infection was examined using an intestinal helminth infection with the parasite Heligmosomoides polygyrus. Adipose tissues predominantly contained regulatory T cells, invariant natural killer T cells and group 2 Innate Lymphoid Cells (ILC2s). Significant differences were observed in composition, cell surface markers and cytokine production of ILC2s between adipose depots and secondary lymphoid tissues, indicating that tissue specific signals can direct ILC2 responses. Finally, increases were observed in ILC2 and FALC numbers in the mesenteries of WT mice following parasite infection. These data indicate that immune cells within adipose tissues respond to infection and may contribute to immune responses.
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SINGH, REETIKA. "COMPARATIVE ANALYSIS OF DIFFERENT CURCUMIN ANALOGUES TO INHIBIT TLR4 EXPRESSION IN BREAST CANCER- AN IN-SILICO STUDY." Thesis, DELHI TECHNOLOGICAL UNIVERSITY, 2021. http://dspace.dtu.ac.in:8080/jspui/handle/repository/18459.
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Chronic inflammation is closely related to the emergence of a number of cancers,
including Breast cancer. Inflammation causes damage to the cell’s DNA which leads
to its abnormal growth and formation of tumor mass. One of the most commonly
known receptor responsible for inflammatory reactions is Toll-like receptor 4
(TLR4). It is activated majorly by bacterial LPS. Its activation further activates
Cyclooxygenase enzyme that catalyzes the conversion of arachidonic acid into
prostaglandins that lead to inflammation-like conditions. COX2 has also been
correlated to the promotion of tumor growth. It enhances metastasis, neoplasia,
lymphangiogenesis, etc., and is also related to poor prognosis in the breast cancer
patients. Curcumin derived from turmeric is a proven inhibitor of COX2. In my
project I have aimed to analyse and compare the inhibitory properties of other
analogues of curcumin that have previously been known to inhibit COX2. The
experimental layout began with screening the molecules on the basis of drug-likeness
using Lipinski rule of five. The suitable ligand molecules were further subjected to
other experiments, i.e., ligand docking and drug potential assessment. After all the
experiments, out of the five selected Curcumin analogues, Isoeugenol (extracted
from clove) was determined as the best fit molecule. The druglikeliness and drug
potential assessment results further validate its use as a potential inhibitor and can
further be tested for in-vivo efficacy. This drug can further be used in the 1st line
therapy of locally advanced and metastatic breast cancer patients as it will inhibit
COX2 that promotes metastasis of cancer cells. Isoeugenol extracted from Eugenia
caryophyllus (Cloves) can further be proven as a better COX2 inhibitor than its
chemical counterparts, as it is a natural compound and will therefore have
significantly less side effects.
8
Wassall, Heather Jane Haining. "Dietary influences and immune regulation of neonatal immune responses to allergens." Thesis, University of Aberdeen, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485812.
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The prevalence of asthma and atopic disease in general, has been increasing in the past forty years, with the UK having one of the highest rates in the world. There have been many theories proposed to explain these increases, but no definitive answer has been found, as yet. Dietary hypotheses suggest that the recent increases in asthma and atopic disease are a consequence of changing dietary lipid intake and lor decreasing dietary antioxidant intake. This hypothesis has been supported by local work, which- has demonstrated that a maternal diet deficient in some antioxidants may influence childhood Th-cell differentiation towards the Th2 phenotype in vitro. Previously, it was thought that Th1 cells regulated Th2 cells. However, it is now thought that Th2 responses may be regulated by other cells, such as Tregulatory cells, (Tr-cells) that have the potential to be involved in the immunopathogenesis ofasthma and atopic disease. . The aims of this project were to characterise -the effects of direct antioxidant and lipid supplementation on umbilical cord blood Th-cells in vitro, and to determine whether the proliferative and cytokine responses of cord blood mononuclear cells, (CBMC) after stimulation with allergens, were mediated through regulatory T-cells. Supplementation with vitamin E, vitamin C or a.-linolenic acid was performed on 135 neonatal cord blood samples. Cell proliferation was quantified 5,6 and 7 days, after stimulation with mitogen, control antigens and allergens, by incorporation of 3H-thymidine into triplicate lOO~1 aliquots drawn from the cultures. Production of the Th1 and Th2 cytokines IFN-y and IL-4, and the regulatory cytokines IL-IO and TGF-13 were measured by a sensitive cellular ELISA adapted for use with CBMC. Flow cytometry was used to identify the phenotype ofTr-cells, by staining for surface antigens and intracellular cytokines. This project has demonstrated that direct supplementation of cord blood Th-cells with vitamin E, vitamin C and a.-linole,nic acid, does influence proliferative and cytokine responses to control stimuli and allergens. Specifically, these nutrients are associated with a general suppression of CBMC proliferative responses to control stimuli and the allergen house dust mite. In contrast, the two vitamins are associated with an increase in CBMC proliferative responses to the allergen, timothy grass pollen. Supplementation is also associated with a general decrease in IFN-y and TGF-13 secretion, with varying effects on IL-IO and IL-4 secretion. This work has also confirmed the presence of functional Tr-cells in neonatal blood at birth. The phenotype of these Tr-cells varies, with cells expressing various combinations and numbers of the three Tr-cell markers; CD25+high, Foxp3 and IL-IO. Allergen stimulation appears to induce Tr-cells in the greatest amounts. In conclusion, this project has demonstrated, for the first time, that direct supplementation of CBMC, with vitamins E and C, and the PUFA, a-linolenic acid, does influence cord blood Th-cell proliferative and cytokine responses to control stimuli and allergens, altering the balance of Th-cell subsets, and suggests that manipulation of maternal diet during pregnancy could modulate neonatal immune responses to allergens and the development of asthma and atopic disease. It has also confirmed the presence of functional Tr-cells in neonatal blood at birth, with variability in numbers between individuals, upon allergen stimulation. The variability in Tr-cell activity associated with allergen stimulation may be linked to the development ofatopic disease in later life.
9
Macaulay, R. "The role of immune inhibitory receptors in age-associated immune decline." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1317772/.
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The balance between signals delivered by positive and negative costimulatory molecules is crucial to the ultimate fate of cellular immune responses. Manipulation of T cell costimulatory pathways may offer a novel approach for reinvigorating exhausted T cell responses, especially in the context of chronic infections. T cells also display profound exhaustion in old age and this thesis investigates the hypothesis that T cell inhibitory receptor upregulation may define a reversible defect in age onset immune decline. Data presented here illustrate how T cells utilise different inhibitory receptors as they differentiate and that KLRG1 signalling is causative of dysfunctions in highly differentiated CD8+ T cells. The inhibitory receptors KLRG1 and CTLA-4 are revealed to undergo age-associated upregulations on CD8+ T cells but their blockade does not reverse the characteristic hypo-responsiveness of CD8+ T cells amongst old donors. The dysregulated immune response to lifelong chronic cytomegalovirus (CMV) infection is thought to play a major role in driving age related immune dysfunctions. We found that CMV accelerates age-associated telomere attrition amongst CD8+ and CD4+ T cells. CMV infection is also shown to drive CTLA-4, PD-1 and KLRG1 upregulation on both CD4+ and CD8+ T cells. Moreover, the PD-1/Ligand (L) inhibitory pathway defines a reversible proliferative dysfunction in the responses of CMV specific CD8+ T cells. Specifically, the CD45RA re-expressing memory subset exhibits a proliferative deficiency, relative to their central and effector memory counterparts, that is reversible upon PD-L blockade. However, this augmented proliferative response was not accompanied by increased telomerase function, suggesting this does not result in true reversal of exhaustion. In summary, the dysfunctions of highly differentiated and CMV specific CD8+ T cells can be at least partially reversed by perturbation of inhibitory receptor pathways, whose further manipulation may provide a therapeutic modality to combat age-associated immune decline.
10
Dehus, Oliver. "Receptor polymorphisms and non-classical immune stimuli in bacterial immune recognition." [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:352-opus-61639.
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Msallam, Rasha. "Intravital imaging and immuno-regulatory functions of mast cells in cutaneous immune responses." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015PA05T019.
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La peau est un « avant poste » fascinant du système immunitaire. Elle forme une barrière entre l'environnement extérieur et l’organisme. Elle est aussi le point d'entrée pour les agents pathogènes, contre lesquels le système immunitaire organise des réponses adaptatives. Les acteurs de l'immunité innée de la peau contrôlent l'invasion des pathogènes et perçoivent également des changements environnementaux physiques et chimiques directs. Plusieurs composants du système immunitaire, tels que des cellules dendritiques (DCs), les macrophages (MΦ) et les mastocytes (MCs), participent à l'éradication des pathogènes et à l'initiation des réponses mémoires adaptatives. Ce qui permet une mobilisation rapide des cellules T effectrices ainsi que la sécrétion des anticorps par les cellules B à la suite d’une seconde exposition aux agents pathogènes. Les MCs qui sont des cellules résidentes du derme, jouent un rôle déterminant dans la libération de signaux d’alertes et sont classiquement considérés comme des cellules effectrices de la réaction allergique cutanée liée à l'IgE. Plusieurs observations récentes indiquent que les MCs seraient aussi impliqués dans les processus immunorégulateurs lors de l'initiation des réponses immunitaires adaptatives, dans le maintien de la tolérance périphérique aux composants de la peau et dans la régénération de la peau au cours des processus de cicatrisation. Cependant, les interactions entre les MCs et d'autres cellules immunitaires innées et adaptatives recrutées dans des conditions inflammatoires cutanées n'ont pas été élucidées en détail. Dans ce travail, nous décrivons l'utilisation d'une nouvelle souris possédant des MCs fluorescents (RMB), dans laquelle nous avons marqué les MCs FcεRI+ avec un marqueur fluorescent rouge tomato (TdT) et avec un système d'ablation conditionnelle basé sur l'expression concurrente du récepteur de la toxine diphtérique (DTR). Avec ces souris RMB, nous avons visualisé la dynamique des MCs et nous avons suivi les interactions entre les MCs et les lymphocytes T régulateurs (Tregs) après l'activation des MCs par l'IgE, dans une réaction inflammatoire typique de l'anaphylaxie cutanée passive (PCA). Dans un second volet d’étude, nous avons évalué le rôle des MCs lors d'un modèle expérimental de la greffe de peau de l'oreille, afin de révéler leur influence dans la cinétique de rejet ou prise de greffe du transplant. Nous avons constaté que 1) l'activation et la dégranulation des MCs induites par le pontage du récepteur FcεRI via des IgE couplées à un antigène multivalent sont les seules responsables de la réaction de PCA, et induisent le recrutement de Tregs ayant une grande motilité sur le site de l'inflammation. Nous avons constaté dans ces conditions, que les MCs restent immobiles, et que les Tregs établissent des contacts dynamiques avec les MCs dans le derme. 2) En outre, nous avons mis en place un modèle pour identifier les paramètres moléculaires de l'interaction MC-Treg et avons constaté que le complexe de l'antigène avec l'IgE peut être présenté aux Tregs en association avec les molécules du complexe majeur d'histocompatibilité de classe II, permettant la formation des contacts stables MC-Treg. 3) En utilisant un modèle de transplantation de la peau in vivo, nous avons montré que l'ablation conditionnelle des MCs conduit à une accélération du rejet du greffon dans le cas d'une transplantation en présence d’une disparité d’antigènes d’histocompatibilité mineurs depuis une souris mâle sur une souris femelle. Nous avons également constaté un impact inattendu de l'ablation des MCs dans la greffe de peau en l’absence de disparité antigénique d'une souris femelle sur une souris femelle, conduisant à un rejet rapide. Les MCs semblent donc être essentiels pour la cicatrisation et la régénération tissulaire après greffe. (...)The skin is a fascinating outpost of the immune system. It performs a barrier function between the outside environment and the inner body and is also a port of entry for pathogens against which the immune system mounts adapted responses. The skin innate immune defenses control pathogen invasion and perceive also direct physical and chemical environmental changes. Several component of the immune system such as dendritic cells (DC), macrophages (MΦ) and mast cells (MC) participate in initial pathogen clearance and in initiating adaptive memory responses, allowing rapid mobilization of effector T cells and secretion of B cellderived antibodies after secondary pathogen challenge. MCs residing in the dermis exert a determinant alert function through the liberation of various factors and are classically considered as effector cells in the IgE-mediated cutaneous allergic reaction. As emerging now, MC are also involved in immunoregulatory processes during the initiation of adaptive immune responses, the maintenance of peripheral tolerance to skin components and skin regeneration during wound healing. Yet, the crosstalks between MCs and other innate and adaptive immune cells recruited during cutaneous inflammatory conditions have not been elucidated in detail. Here, we report the use of a novel Mast cell fluorescent reporter mouse (RMB), in which we tagged FcεRI+ MCs, with red fluorescence marker tomato (Tdt) and with a conditional ablation system based on concurrent diphtheria toxin receptor (DTR) expression. Using these RMB mice, we visualized MC dynamics and monitored MC interactions with regulatory T lymphocytes (Tregs) after IgE-mediated activation of MCs, in a typical passive cutaneous anaphylaxis (PCA) inflammatory reaction. Using another setting, we further assessed the role of MC during experimental ear skin grafting to reveal their potential influence in skin grafting and rejection. We found that 1) the activation and degranulation of MCs induced by FcεRI crosslinking by multivalent IgE is solely responsible for the PCA reaction and induces the recruitment of highly motile regulatory T cells (Tregs) to the site of inflammation. In these conditions, we found that MC remain sessile and Tregs establish dynamic contacts with MC in the dermis. 2) Further we set up a model system to reveal the molecular requirement for MC-Treg interaction and found that antigen complexed with IgE were able to be presented to Treg in association with major histocompatibility complex class II molecules allowing the formation of stable MC-Treg contacts. 3) Using in vivo skin transplantation model, we showed that conditional ablation of MCs leads to an acceleration of skin transplant rejection in sex-mismatched model (male skin transplant to female). We also found an unexpected impact of MC conditional ablation in sex-matched skin graft (female skin transplant to female) leading to rapid rejection, implying that MCs are essential for the wound healing reaction and the regeneration of tissue continuity after grafting. The aforementioned results point out to an important immunoregulatory role of MC beyond their classically described activator functions in inflamed tissues. The fact that MC constantly interact with Treg during inflammatory processes suggest that MCs could participate in skin homeostasis by exerting tolerogenic functions. These functions remain to be elucidated at the molecular level as presented in the discussion
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Aryee, Ken-Edwin. "Utilizing Humanized Mice to Study Human Specific Innate Immune Responses in Immuno-Oncology." eScholarship@UMMS, 2019. https://escholarship.umassmed.edu/gsbs_diss/1041.
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The kinetics of tumor growth and progression are governed by the interaction between tumor cells, the non-malignant stroma and both innate and adaptive immune cell lineages. Innate immunity has a critical role in the control of tumor cell growth and metastasis. The microenvironment of many tumors is populated with innate immune cells, including regulatory natural killer (NK) cells and dendritic cells (DCs), tumor associated macrophages, and myeloid derived suppressor cells, that suppress normal immune function. Much of our understanding of interactions between tumors and the innate immune system is based on experimental studies performed in mouse “syngenic” models. However, there is clear need for a mechanistic understanding of the human innate immune system within the tumor microenvironment.
The goal of my thesis is to characterize the interactions between human innate immune cells and tumors and to define specific pathways and cell lineages that are targets for immune modulation. A central focus of my thesis is the use of cutting-edge humanized mouse models based on the immunodeficient NOD-scid IL2Rgnull (NSG) mouse strain to study human immuno-oncology. In the first section of my thesis I describe studies that evaluate the influence of inflammatory stimuli on innate immune control of tumors. Agents that induce inflammation have been used since the 18th century for the treatment of cancer. The inflammation induced by agents such as toll-like receptor (TLR) agonists is thought to stimulate tumor-specific immunity in patients and augment control of tumor burden. While NSG mice lack murine adaptive immunity (T and B cells), these mice maintain a residual murine innate immune system that responds to TLR agonists. Here I describe a novel NSG mouse strain lacking TLR4 that fails to respond to lipopolysaccharide (LPS). NSG-Tlr4null mice support human immune system engraftment and enables the study of human specific responses to TLR4 agonists. My data demonstrate that specific stimulation of TLR4 activates human innate immune system and promotes regression of human patient derived xenograft (PDX) tumors. In the second section of my thesis I describe the development of an NSG mouse strain that constitutively expresses human Interleukin 15 (IL15) and supports the development of functional human NK cells. Using humanized NSG-IL15 transgenic mice (NSG-Tg(Hu-IL15), my data clearly demonstrate a critical role for human NK cells in limiting growth of a PDX melanoma. In the third section of my thesis I describe, the use of the bone marrow/liver/thymus (BLT) humanized mouse model to study the interactions between the human immune system and PDX melanoma and to evaluate the response of the melanoma to immunotherapy modalities.
My results collectively suggest that mice engrafted with human immune systems and bearing human tumors can be harnessed as translational models, which are critically needed as tools to study tumor immunotherapy. These humanized mouse models are an ideal translational tool to advance our understanding of human immuno-oncology and for development and testing of novel immune therapies for the treatment of malignancies.
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Ozanne, Alexandra. "Activation immunitaire, immuno-sénescence et inflammation : Analyses statistiques des liens avec les comorbidités non liées au VIH lors de l’infection par le VIH." Thesis, Bordeaux, 2017. http://www.theses.fr/2017BORD0846/document.
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Les thérapeutiques antirétrovirales ont permis d’augmenter la survie des personnes vivant avec le VIH (PVVIH). Cependant, de nombreuses comorbidités non liées au VIH émergent et sont une préoccupation majeure dans la prise en charge des patients. L’activation, l’inflammation et l’immunosénescence pourraient jouer un rôle majeur dans ce processus. De nombreux marqueurs existent pour mesurer ces dysfonctionnements et ils ont souvent été considérés sans prendre en compte leurpossible interdépendance. Les objectifs de cette thèse était i) de proposer une combinaison de ces marqueurs, ii) d’évaluer l’association entre la combinaison de ces marqueurs et la présence des comorbidités, et iii) d’évaluer l’association entre la combinaison de ces marqueurs, et le risque de survenue des comorbidités et de la mortalité chez des PVVIH inclus dans la sous étude CIADIS de la cohorte ANRS CO3 Aquitaine. Nous avons identifié deux scores : le score CIADIS cellulaire et soluble. Le score cellulaire était plutôt associé à la multimorbidité et à la survenue d’une nouvelle comorbidité quelle qu’elle soit. Le profil des dysfonctionnements immunitaires sous-jacent était différent lorsque l’on s’intéressait aux comorbidités séparément. Ces résultats soutiennent l’hypothèse que différents profils d’activation, d’inflammation et de sénescence sous-jacents pourraient être impliqués dans le développement de différentes comorbidités. Nos résultats montrent que des analyses intégrant de nouveaux biomarqueurs pourraient accroître la compréhension des comorbidités. Nous allons continuer de travailler sur l’identification des profils de dysfonctionnements immunitaires pour des comorbidités spécifiquesAntiretroviral therapies have improved the survival of HIV-infected people. However, many non-HIVrelated comorbidities occur and represent a major concern in patient care. Activation, inflammation and immunosenescence could play a major role in this process. Many markers can measure those dysfunctions and they are often used without accounting for their possible interdependency. The objectives of this thesis were i) proposing a combination of those markers, ii) assessing the association between the combination of markers and the presence of comorbidities and iii) assessing the association between the combination of markers and the risk of occurrence of comorbidities and mortality in HIV-infected patients included in the sub-study CIADIS from cohort ANRS CO3 Aquitaine. We identified two scores: the cellular and the soluble CIADIS scores. The cellular score was mostly to multimorbidity and occurrence of any kind of new comorbidity. The profile of underlying immune dysfunctions was different when looking separately at the comorbidities. These results support the assumption that several underlying profiles of activation, inflammation and senescence could be involved in the development of different comorbidities. Our results show that integrating new biomarkers in analyses could improve the understanding of comorbidities. We will continue to work on the identification of profiles of immune dysfunctions for some specific comorbidity
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Thapa, Navin. "Immune parameters in mycobacterioses, other immune disorders and the effects of immunotherapy." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313617.
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Marri, Eswari. "Immune surveillance of activated immune and tumour cells by surfactant protein D." Thesis, Brunel University, 2015. http://bura.brunel.ac.uk/handle/2438/13847.
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Surfactant protein D (SP-D) is a carbohydrate/charged pattern recognition molecule of the innate immune system. By virtue of its ability to recognize an array of carbohydrate patterns on the surface of a range of pathogens, SP-D can bring about opsonisation, enhanced phagocytosis and killing of a diverse range of viruses, bacteria and fungi. In addition to antimicrobial functions, which also includes bacteriostatic and fungistatic properties SP-D has also been shown to bind allergens derived from a number of sources including house dust mite, Aspergilllus fumigatus and pollen grains. SP-D allergen interaction leads to inhibition of specific IgE binding and subsequent downregulation of histamine release from sensitized basophils and mast cells. Thus, a number of murine models of pulmonary hypersensitivity and allergic asthma induced by ovalbumin, house dust mite and Aspergillus fumigatus allergens/antigens have been tested for the ability of SP-D to dampen allergic symptoms on the immunological parameters. In general, treatment of allergic models with a recombinant fragment of human SP-D (rh SP-D; composed of trimeric, neck and carbohydrate recognition domain) has been shown to cause downregualtion of specific IgE synthesis, pulmonary and peripheral eosinophilia and airway hyper reactivity, and Th2→Th1 polarisation. However, therapeutic alleviation of eosinophilia by rh SP-D treatment became evident when SP-D gene deficient mice were found to be hypereosinophilic In fact, rhSP-D binds well to eosinophils derived from allergic patients and induces apoptosis without affecting eosinophils derived from healthy individuals or non-activated/non-sensitized eosinophils. Proteomic analysis of rh SP-D treated eosinophillic cell line that revealed that apoptosis induction takes place via p53 pathway. In this thesis, proteomic signatures were replicated using a leukemic cell line AML14.3D10 via qPCR analysis by identifying targets from a spectrum of genes, which were either upregulated or downregulated. It appears that in spite of induction of apoptosis by rh SP-D, different cells respond differentially at molecular levels (Chapter 3). Sensing that SP-D can induce apoptosis in altered or transformed cells; the effect of SP-D gene expression within pancreatic cancer cells was also investigated. The experiments confirmed p53 pathway dependence for suppression of cancer. Interestingly, factors responsible for metastasis for cancer are also downregulated by endogenous overexpression of SP-D, as validated by wound healing assay. We conclude that SP-D is a general immunosurveillance molecule, which is involved in the clearance of altered and transformed cells (Chapter 4). Chapter 5 shows a direct interaction between DC-SIGN and rh SP-D that inhibits DC-SIGN interaction of allergens and HIV-1, tow common ligands for SP-D and DC-SIGN. Using transfected human embryonic kidney (HEK) cells expressing surface DC-SIGN, we found that pre-treatment of these cells with rhSP-D suppressed DC-SIGN mediated transmission of HIV-1to co-cultured PBMCs. The effect of rhSP-D-DC-SIGN In conclusion, this thesis highlights a broader immune role of SP-D in homeostasis and probably assigns potential functions of extrapulmonary and/or locally synthesized SP-D within non-lung tissues and blood.
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Wangkahart, Eakapol. "Immune responses of rainbow trout (Oncorhynchus mykiss) to vaccination and immune stimulation." Thesis, University of Aberdeen, 2017. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=233634.
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Vaccination and the use of immune stimulants are two important ways to mitigate the costs of disease in fish aquaculture. A vaccine to Enteric redmouth disease (ERM) was the first licensed fish vaccine in the world. Although effective in protecting fish from the motile bacterial (Yersinia ruckeri) infection, ERM can occur in ERM vaccinated fish due to the rise of non-motile Y. ruckeri that does not express flagellin. This highlighted the need for continual improvement of vaccine efficacy and the importance of flagellin in fish immune responses. In this thesis the immune response to the ERM vaccine was studied first to give insights for vaccine development. A recombinant flagellin from Y. ruckeri (YRF) was then produced and its bioactivities were investigated in vitro and in vivo. The immune response to ERM vaccination was studied in rainbow trout in two major and relevant immune organs, the spleen and gills. Intraperitoneal injection of the ERM vaccine induces an early balanced expression of pro- and anti-inflammatory cytokines and adaptive cytokines in the spleen, with a heightened expression of acute phase proteins (APPs) and anti-microbial peptides (AMPs) in both spleen and gills. The analysis suggests that ERM vaccination activates host innate immunity and the expression of specific IL-12 and IL-23 isoforms leading to a Th1 and Th17 biased immune responses. This study has increased our understanding of the host immune response to ERM vaccination and the adaptive pathways involved. The early responses of a set of genes established in this study may prove useful as biomarkers in future vaccine development in aquaculture. YRF was next produced in a bacterial system, and purified. Its bioactivity was investigated first in the trout macrophage cell line RTS-11 and head kidney primary cell cultures. YRF is a potent activator of pro-inflammatory cytokines, APPs, AMPs and subunits of the IL-12 cytokine family in vitro. This property was further confirm in vivo in multiple tissues after intraperitoneal injection of YRF. These results suggest that flagellins are important pathogen-associated molecular patterns (PAMPs) that can activate an inflammatory response in fish not only in vitro but also in vivo. Furthermore, YRF was shown to be the most potent PAMP in vitro, in terms of activation of an inflammatory response, compared to pure LPS and peptidoglycan. In addition, YRF mixed with complete Freund's adjuvant can induce YRF-specific IgM antibodies in rainbow trout. These antibodies are able to neutralize YRF bioactivity, and react against the middle domain of YRF, as assessed in Western blot analysis. When YRF was fused with a protein antigen, it increased the antigen-specific IgM antibody response. This analysis reveals that YRF is a potent activator of host immune responses and can be used as an immune stimulant and adjuvant to improve vaccine efficacy.
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Gaken, Johannes Adrianus. "The role of immune costimulators in the immune gene therapy of cancer." Thesis, University of Sussex, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297556.
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Ahmed, Ejaz. "Immune mechanisms in atherosclerosis /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4612-4/.
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Juffermans, Nicole Petra. "Immune responses to tuberculosis." [Amsterdam] : Amsterdam : Thela Thesis ; Universiteit van Amsterdam [Host], 2000. http://dare.uva.nl/document/82665.
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Chaithong, Udom. "Immune responses in mosquitoes." Thesis, University of Liverpool, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293724.
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Cain, D. J. "Perioperative neutrophil immune function." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1568022/.
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Within the UK severe sepsis is responsible for 29% of intensive care admissions and carries a mortality of 44.7%. Decades of research have failed to deliver a single clinically successful immune modulating therapeutic agent. These failings may be explained by fundamental methodological challenges of sepsis laboratory investigations, namely diagnostic uncertainty, an indeterminate onset and the identification of an immunologically similar control population. The underlying hypothesis for this thesis is that the translational investigation of surgical patients may overcome many of these methodological challenges, since surgical trauma generates a homogenous inflammatory insult at a planned time to a carefully phenotyped human population. The biological basis for modelling sepsis with traumatic injury is discussed. Firstly, I reviewed the current literature to demonstrate the methodological advantages of studying surgical patients as a surrogate for sepsis. Next, I performed an observational study of neutrophil immune function following major elective surgery which identified a reduced neutrophil respiratory burst and changes in cell surface immune receptor expression. This impairment of activated neutrophil immune function was associated with resting neutrophil mitochondrial dysfunction, namely a raised mitochondrial membrane potential and increased production of reactive oxygen species. Using two different models of mitochondrial dysfunction I demonstrated that neutrophil respiratory burst may be regulated by altered mitochondrial functionality. Finally, I provide evidence that the cytoplasmic target for this mitochondrial signal is the enzyme pyruvate kinase M2, which through oxidative inhibition reduces the production of the respiratory burst substrate NADPH by limiting flow of glucose through the hexose monophosphate shunt. In summary, major elective surgery provides a translational model of human sepsis. Using this model, I demonstrate impairment of the neutrophil respiratory burst, and provide evidence that this is mediated through neutrophil mitochondrial dysfunction which promotes oxidative inhibition of the glycolytic regulatory enzyme pyruvate kinase.
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Erridge, Clett. "Immune responses to lipopolysaccharide." Thesis, University of Edinburgh, 2002. http://hdl.handle.net/1842/23334.
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Close, Helen Judith. "Immune evasion in glioma." Thesis, University of Leeds, 2016. http://etheses.whiterose.ac.uk/16103/.
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Glioblastoma multiforme (GBM) is the most common form of primary brain cancer and the current prognosis for patients is poor. New therapies are required that target the invasive cells that are characteristic of GBM. GBM is infiltrated by immune cells but, as with other cancers, immune evasion pathways minimise productive anti-tumour immunity. Natural killer (NK) cells are able to recognise and kill tumour cells and are being developed for the immunotherapy of other cancers. The aim of this work was to analyse the interaction between human NK cells and GBM cells in vivo and in vitro, as a prerequisite to future NK cell based immunotherapy of GBM. Analysis of the cell surface phenotype for GBM infiltrating NK and T cells revealed that the tumour microenvironment exerts localised immune evasion mechanisms which downregulate activation receptors and upregulate inhibitory receptors. The interaction of NK cells with patient-derived GBM stem cells, which are thought to be responsible for recurrent disease, was investigated in vitro. A high-throughput, multiplex flow cytometry-based screen of tumour cells revealed the expression of a number of cell surface molecules that regulate NK cell activation. Furthermore, GBM cells were more susceptible to NK cell lysis in vitro compared to a non-cancerous neural progenitor cell line, revealing specificity in the NK cell response. Furthermore, this screen identified potential mechanisms by which GBM might evade immune surveillance in vivo. Targeting these pathways and restoring functional immune surveillance provides a potential route for future immunotherapy of this disease. However, GBM patients often experience cerebral oedema and are treated with immunosuppressive corticosteroids, such as dexamethasone; this induces a similar immunosuppressed phenotype to that observed with the GBM infiltrating NK cells, and inhibits their lytic function. Gene expression profiling identified the transcription factor c-Myc as a key regulator of NK cell activation and as a hub for the immunosuppressive action of steroids and the immunosuppressive cytokine TGF-β. The demonstration that therapeutic steroids target the same pathway as TGF-β and induce immunosuppression has important implications for the use of steroids in patients undergoing immunotherapy.
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Steinfelder, Svenja. "Immune modulation by parasites." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2007. http://dx.doi.org/10.18452/15682.
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Die Infektion mit Schistosoma mansoni resultiert in einer Th2-Immunantwort mit Eosinophilie und erhöhtem IgE-Titer, wobei der wasserlösliche Extrakt der S. mansoni Eier (SEA) ausreicht um diese Reaktion auszulösen. In der vorliegenden Arbeit konnte demonstriert werden, dass sich IL-4-produzierende CD4+ T-Lymphozyten in Zellkulturen mit SEA-konditionierten Dendritischen Zellen (DCs) trotz gleichzeitig vorkommenden IFN-gamma entwickeln und SEA die Expression von Faktoren in DCs, die üblicherweise mit einer Th1-Antwort einhergehen, auf Transkriptions- und Proteinebene selektiv hemmt. Um den Faktor aus S. mansoni Eiern zu isolieren, der zur Expression von IL-4 in CD4+ Zellen und zur Inhibition von IL-12 in DCs führt, wurde eine Gelfiltrationschromatographie der exkretorisch/sekretorischen Ei-antigene (ES) durchgeführt und die Fraktionen in vitro getestet. Darin wurde gezeigt, dass Fraktionen mit einer Proteinbande von 30 kD die Expression von IL-4 in CD4+ Zellen induzieren. Dieses ES-Protein wurde durch N-terminale Sequenzierung als hepatotoxische Ribonuclease Omega-1 identifiziert, welches ebenfalls die Expression von IL-12 in DCs inhibiert und die Produktion von IL-4 in CD4+ Zellen bei einer 10-fach geringeren Proteinkonzentration als mit dem Kontrollansatz SEA induziert. Zudem sollte untersucht werden, inwieweit Toll-like Rezeptoren in der Generierung einer Th2 Antwort gegen schistosomale Antigene involviert sind. Dazu wurden TLR2-, TLR3-, TLR4- und MyD88-defiziente Mäuse mit S. mansoni infiziert und immunologische und pathologische Daten in der akuten und chronischen Phase der Infektion analysiert. Demnach sind TLR2, TLR3, TLR4 und MyD88-abhängige Signaltransduktionswege nicht für eine-Th2 Antwort notwendig, jedoch ist letzteres Molekül in der Ausprägung der typischen Leberfibrose involviert.Infection with Schistosoma mansoni results in the induction of a Th2 immune response, eosinophilia and increased levels of IgE. The water-soluble extract of S. mansoni eggs (SEA) is sufficient to promote TH2 polarization in a dendritic cell-dependent manner. In this thesis, it was demonstrated that IL-4+ CD4+ cells emerge in cultures with SEA-conditioned dendritic cells (DCs) in the presence of IFN-gamma and that SEA inhibits selectively the expression of IL-12 and co-stimulatory markers in DCs on the transcriptional and protein level. To identify the putative protein in S. mansoni eggs mediating a Th2 induction, a gel filtration chromatography of the excretory/secretory egg antigens (ES) was conducted and the fractions tested in vitro. Fractions containing a single band of 30 kD were sufficient to promote IL-4 induction in naïve CD4+ cells. Using N-terminal sequencing this ES-protein was identified as the hepatotoxic S. mansoni ribonuclease omega-1 which displayed both biological functions observed with SEA: inhibition of IL-12 in LPS-stimulated DCs and induction of IL-4+ CD4 cells at a 10 fold lower protein concentration than SEA. In order to understand, if the innate immune receptors TLR2, TLR3, TLR4 or the TLR adaptor molecule MyD88 are involved in the generation of the Th2 response against schistosomal antigens, the respective knock out mice were infected and immunological and pathological parameters were analyzed during acute and chronic phase of infection. This study showed that during S. mansoni infection TLR2, TLR3, TLR4 and TLR activation through the MyD88-dependent pathway are neither required for the induction (priming and polarization) nor for the down-regulation of Th2 responses, however, the fibrotic response against S. mansoni eggs was significantly reduced in MyD88-deficient mice suggesting a detrimental role of this pathway in liver pathology.
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Moro, Monica. "Manipulation of anti-tumour immune response by tumour targeting with soluble immuno-modulatory molecules." Thesis, Open University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323271.
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Warnatsch, Annika. "Impact of proteasomal immune adaptation on the early immune response to viral infection." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2013. http://dx.doi.org/10.18452/16775.
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Im Kampf gegen eine Virusinfektion spielen CD8+ T Zellen des adaptiven Immunsystems eine besondere Rolle. Sie patroullieren im Körper und entdecken spezifische Virusepitope, welche mittels MHC Klasse I Molekülen auf der Oberfläche infizierter Zellen präsentiert werden. Wird eine virus-infizierte Zelle erkannt, kann diese schnell und effizient eliminiert. Für die Generierung viraler Peptide, welche auf MHC Klasse I Komplexe geladen werden, ist das Ubiquitin-Proteasom-System von essentieller Bedeutung. Kürzlich wurden weitere Funktionen des Immunoproteasoms aufgedeckt wie zum Beispiel der Schutz gegen oxidativen Stress. Innerhalb der vorliegenden Arbeit konnte die Fähigkeit des Immunoproteasoms gegen eine Akkumulation oxidativ geschädigter Proteine zu schützen mit der Generierung von MHC Klasse I Liganden kombiniert und neu interpretiert werden. Es konnte gezeigt werden, dass während einer Virusinfektion in Nicht-Immunzellen die Produktion reaktiver Sauerstoffspezies durch die alternative NADPH Oxidase Nox4 eine bedeutende Rolle spielt. Die Aktivierung von Nox4 resultiert in der Akkumulation oxidativ geschädigter Proteine. Innerhalb von zwei Stunden nach dem Eintreten von Viruspartikeln in die Zellen wurden strukturelle Virusproteine oxidiert und anschließend ubiquityliert. Die gleichzeitige, virus-induzierte Expression von Immunoproteasomen führte zu einem schnellen und effizienten Abbau ubiquitylierter Virusantigene. Infolgedessen konnten immundominante Virusepitope vermehrt freigesetzt werden. Folglich wurde ein soweit unbekannter Mechanismus gefunden, welcher Substrate für das Proteasom zur Generierung von MHC Klasse I Liganden bereitstellt. Zusammenfassend konnte innerhalb dieser Arbeit gezeigt werden, dass das Immunoproteasom den Schutz vor oxidativen Stress mit der Generierung antigener Peptide verbindet, wodurch eine effektive adaptive Immunantwort etabliert werden kann.An efficient immune control of virus infection is predominantly mediated by CD8+ T cells which patrol through the body and eliminate infected cells. Infected cells are recognized when they present viral antigenic peptides on their surface via MHC class I molecules. To make antigenic peptides available for loading on MHC class I complexes, the ubiquitin proteasome system plays a crucial role. Moreover, the induction of the i-proteasome is known to support the generation of MHC class I ligands. Recently, new functions of the i-proteasome have been discovered. Evidence is increasing that the i-proteasome is involved in the protection of cells against oxidative stress. Within this thesis the characteristic of the i-proteasome to protect cells against the accumulation of oxidant-damaged proteins could be linked to its role in improving the generation of MHC class I ligands. It could be demonstrated that during a virus infection in non-immune cells the production of reactive oxygen species by the alternative NADPH oxidase Nox4 is of critical importance resulting in the accumulation of potentially toxic oxidant-damaged proteins. Indeed, within two hours of infection structural virus proteins were oxidized and subsequently poly-ubiquitylated. The concomitant formation of i-proteasomes led to a rapid and efficient degradation of ubiquitylated virus antigens thereby improving the liberation of immunodominant viral epitopes. In conclusion, a so far unknown mechanism to fuel proteasomal substrates into the MHC class I antigen presentation pathway has been revealed. A new protein pool consisting of exogenously delivered viral proteins provides proteasomal substrates in the very early phase of a virus infection. Within the scope of this thesis the i-proteasome has been shown to link the protection against oxidative stress, initiated directly by pathogen recognition, with the generation of antigenic peptides. Together, an effective adaptive immune response is triggered.
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Mayer, Andreas. "Optimal immune systems : a ressource allocation and information processing view of immune defense." Thesis, Paris Sciences et Lettres (ComUE), 2017. http://www.theses.fr/2017PSLEE026/document.
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Les organismes biologiques ont développé divers mécanismes immunitaires afin de se protéger des pathogènes. Nous développons ici des modèles mathématiques de systèmes immunitaires, adaptés de façon optimale aux statistiques des pathogènes. Au delà des détails moléculaires, ces mécanismes immunitaires diffèrent dans la manière d'acquérir, de réguler et de transmettre une protection immunitaire ; différences qui pourraient s'avérer essentielles pour la survie à long terme. Afin d'expliquer la diversité des stratégies qui sont observées, nous comparons l'adaptation à long terme de populations en fonction de la dynamique des pathogènes à laquelle elles sont confrontées et de la stratégie immunitaire qu'elles adoptent. Nous démontrons que la fréquence et l'échelle de temps caractéristique des pathogènes sont les deux déterminants clés d'une stratégie immunitaire optimale. En fonction de ces deux paramètres, nous identifions des modes d'immunité distincts, comprenant immunités innées, adaptatives, ou ressemblant au système CRISPR, qui récapitulent la diversité de systèmes immunitaires naturels. Nos résultats viennent s'étendre à la question générale de l'évolution dans des environnements variables pour laquelle nous apportons de nouveaux résultats analytiques au sein d'environnements temporairement corrélés. Le système immunitaire adaptatif assure une protection à partir d'un large répertoire de cellules spécifiques à différents pathogènes. Pour prédire des propriétés statistiques de répertoires adaptés, nous étudions quel répertoire minimise au mieux le risque d'infections pour une distribution de pathogènes donnée. La théorie prédit que les cellules spécifiques contre les antigènes rares sont surreprésentées par rapport à la fréquence de leurs rencontres et que les individus, exposés aux mêmes infections, possèdent des répertoires avec des récepteurs largement différents mais exploitent la réactivité croisée afin de parvenir à la même couverture d'antigènes. Nos résultats sont issus d'une opposition entre les statistiques de détection des pathogènes, qui soutiennent l'idée d'une plus large distribution de récepteurs, et les effets de la réactivité croisée, qui tend à concentrer le répertoire optimal sur un petit nombre de clones. Nos prédictions peuvent être testées à partir d'enquêtes à haut débit sur la diversité des récepteurs et de pathogènes. Par la suite, nous examinons explicitement comment le système immunitaire adaptatif peut apprendre de manière bayésienne les statistiques de l'environnement à partir de l'historique des infections précédentes. Nous montrons que les répertoires optimaux peuvent être atteints par prolifération sélective des cellules spécifiques. La perspective bayésienne sur la dynamique des répertoires fournit un cadre conceptuel unificateur qui explique un certain nombre de caractéristiques de la mémoire immunitaire et appelle à des expériences complémentairesBiological organisms have evolved diverse immune mechanisms to defend themselves against pathogens. Here we build mathematical models of immune systems optimally tuned to the statistics of pathogens. Beyond molecular details, different immune mechanisms differ in how protection is acquired, processed and passed on to subsequent generations -- differences that may be essential to long-term survival. To explain the observed diversity of strategies we compare the long-term adaptation of populations as a function of the pathogen dynamics that they experience and of the immune strategy that they adopt. We find that the two key determinants of an optimal immune strategy are the frequency and the characteristic timescale of the pathogens. Depending on these two parameters, we identify distinct modes of immunity, including adaptive, innate, bet-hedging and CRISPR-like immunities, which recapitulate the diversity of natural immune systems. Our results carry over to the general question of evolution in fluctuating environments, for which we provide novel analytical results in temporally correlated environments. The adaptive immune system provides protection through a broad repertoire of cells specific to different pathogens. To predict statistical features of well-adapted repertoires we analyze which repertoire minimizes cost of infection for a given distribution of pathogens. The theory predicts that the immune system has more receptors for rare antigens than expected from the frequency of encounters; and individuals exposed to the same infections have sparse repertoires that are largely different, but nevertheless exploit cross-reactivity to provide the same coverage of antigens. Our results follow from a tension between the statistics of pathogen detection, which favor a broader receptor distribution, and the effects of cross-reactivity, which tend to concentrate the optimal repertoire onto a few highly abundant clones. These predictions can be tested in high throughput surveys of receptor and pathogen diversity. We then explicitly consider how the adaptive immune system can learn the statistics of the environments from its past infection history in a Bayesian manner. We show that optimal repertoires can be reached by keeping memory of an infection through the selective proliferation of stimulated cells. The Bayesian perspective on repertoire dynamics provides an unifying conceptual framework to explain a number of features of immunological memory and suggests further experiments
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Urrutia, Alejandra. "Defining the boundaries of a healthy immune response using standardized immune monitoring tools." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066004/document.
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Le projet Milieu Intérieur a pour but d'identifier les facteurs génétiques et environnementaux ayant un impact sur la variabilité immunitaire naturelle. Cette analyse multiparamétrique requière néanmoins d'utiliser des outils standardisés. Afin d'étudier la réponse immune induite, nous avons utilisé un système optimisé prêt à l'emploi de stimulation du sang et développé un protocole unique de quantification de l'ARN afin d'étudier la signature transcriptionnelle en réponse à des immuno-modulateurs. Testant l'hypothèse que la réponse à des composés complexes peut être définie par la signature ARN de cytokines clefs et utilisant une méthode statistique robuste, nous avons identifié 44 gènes capables d'optimiser la capture de la réponse à des stimulations plus complexes aidant à la réduction dimensionnelle pour la décomposition de réponses innées. Dans une seconde étude, l'analyse semi-automatisée par cytomètrie en flux des cellules du sang a été associée à l'analyse épidémiologique et génotypique pour les 1,000 donneurs inclus dans la cohorte. Nous avons observé que le tabac, l'âge, le genre et l'infection latente par le cytomégalovirus sont les facteurs impactant le plus la variabilité immunitaire. Cette étude a montré que les paramètres des cellules innées sont contrôlés par des facteurs génétiques alors que ceux des cellules adaptatives le sont plutôt par des expositions environnementales tout au long de la vie. Des outils interactifs incluant ces données de référence accompagnent ces études. Ces analyses montrent que nous avons développé des outils performants pour une étude intégrative du modèle humain constituant une approche innovante vers une médecine personnaliséeThe project Milieu Intérieur aims to study the genetic and environmental factors that can have a major impact on occurring immunological variance in healthy human population. This characterization requires the use of standardized immunophenotyping technologies for integrating diverse, complex datasets. With this goal in mind, we used an optimized suite of standardized whole-blood stimulation systems to study the human induced immune response in physiological condition and developed a unique standardized protocol to analyze the ARN signatures upon whole-blood stimulation to test the hypothesis that responses to complex stimuli can be defined by the transcriptional signatures of key cytokines. We found 44 genes, identified using Support Vector Machine learning, which captured the diversity of complex innate immune responses with improved segregation between distinct stimuli. This provides new strategies for dimension reduction of large datasets and for deconvolution of innate immune responses, applicable for characterizing novel immunomodulatory molecules.In a second related study, we aimed to identify the environmental and genetic factors driving innate and adaptive immune cell parameters in homeostatic conditions. To do so, we combined semi-automated flow cytometric analysis of blood leukocytes and genome-wide DNA genotyping in the 1,000 healthy donors included in the collection. We show that smoking, age, gender and latent cytomegalovirus infection, are main drivers of human variation (i.e. numbers of Treg and MAIT cells). These results demonstrated that innate cell parameters are strongly controlled by genetic factors, whereas adaptive cells are driven by life-long environmental exposures. In addition, to help on the public data mining, we developed interactive R-Shiny application including healthy donor reference values for both studies.All together, these results indicate that we developed powerful tools for human system biology approaches to support personalized medecine
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Shouval, Dror S. "The Role of Innate Immune IL-10 Receptor Signaling in Controlling Intestinal Immune Responses." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17613727.
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Interleukin-10 (IL-10) is a key anti-inflammatory cytokine. Patients with deleterious mutations in either IL10 or its receptor (IL10R) develop severe inflammatory bowel disease (IBD) within the first months of life; similarly, Il10rb-/- mice develop spontaneous colitis. The precise mechanisms of IL-10R-dependent control of immune tolerance and intestinal mucosal homeostasis are not well defined. Here I demonstrate that IL-10R signaling in innate immune cells is critical for regulating mucosal homeostasis and prevention of colitis. Loss of IL-10R-dependent signaling caused wild-type CD4+ T cells to become colitogenic in a murine colitis transfer model. Moreover, My data indicate that IL-10R-dependent signals modulated the differentiation and function of bone-marrow-derived macrophages and intestinal macrophages into either pro-inflammatory macrophages or functionally competent anti-inflammatory macrophages in mice. Similarly, monocyte-derived macrophages from very early onset IBD patients harboring loss of function mutations in IL10RA and IL10RB genes also exhibited impaired differentiation and function of pro- and anti-inflammatory macrophages. These results define a unique and non-redundant role for IL-10R signaling in innate immune cell control of intestinal mucosal homeostasis in mice and humans.
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Smith, Alexia Genese Beck Melinda A. "Obesity alters the immune response to influenza virus infection a mechanism for immune modulation /." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1606.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Sep. 16, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Nutrition, School of Public Health." Discipline: Nutrition; Department/School: Public Health.
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Timmis, Jonathan Ian. "Artificial immune systems : a novel data analysis technique inspired by the immune network theory." Thesis, University of Kent, 2000. https://kar.kent.ac.uk/21989/.
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This thesis presents a novel data analysis technique inspired by the natural immune system. Immunological metaphors were extracted, simplified and applied to create an effective data analysis technique. This thesis builds on foundations of previous work, extracts salient features of the immune system and creates a principled and effective data analysis technique. Throughout this thesis, a methodical and principled approach was adopted. Previous work, along with background immunology was extensively surveyed. Problems with previous research were identified and principles from immunology were extracted to create the initial AIS for data analysis. The AIS, through the process of cloning and mutation, built up a network of B cells that were a diverse representation of data being analysed. This network was visualised via a specially developed tool. This allows the user to interact with the network and use the system for exploratory data analysis. Experiments were performed on two different data sets, a simple simulated data set and the Fisher Iris data set. Good results were obtained by the AIS on both sets, with the AIS being able to identify clusters known to exist within them. Extensive investigation into the algorithm's behaviour was undertaken and the way in which algorithm parameters effected performance and results was also examined. Despite initial success from the original AIS, problems were identified with the algorithm and the second stage of research was undertaken. This resulted in the resource limited artificial immune system (RLAIS) which created a stable network of objects that did not deteriorate or loose patterns once discovered. Periods of stable network size were observed with perturbations of the network size. This thesis presents a successful application of immune system metaphors to create a novel data analysis technique. Furthermore, the RLAIS goes a long way toward making AIS a viable contender for effective data analysis and further research is identified for study.
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BARBERAN, ELISABETH. "Formes frontieres des hepatopathies auto-immunes : cholangite primitive auto-immune ? : a propos de 3 cas." Toulouse 3, 1994. http://www.theses.fr/1994TOU31067.
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Lidehäll, Anna Karin. "Cellular Immune Responses to Cytomegalovirus." Doctoral thesis, Uppsala University, Department of Oncology, Radiology and Clinical Immunology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8578.
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Cytomegalovirus (CMV) is a widespread infection affecting 50-90% of the human population. A typical silent primary infection is followed by life-long persistence in the host under control by virus-specific CD8 (“killer”) and CD4 (“helper”) T cells. Although harmless in most people, CMV may cause disease and sequelae in patients with deficient cellular immunity, such as AIDS patients, recipients of organ transplants and children who have acquired the virus before birth. In this thesis we have characterized the cellular immunity to CMV in immunocompetent subjects, in patients receiving transplants and in infants.
In healthy individuals with latent CMV, the frequencies of CMV-specific CD8 T cells varied considerably between the donors. Within the same individual, the changes over time were usually small. In patients with primary, symptomatic CMV infection, the frequencies of CMV-specific CD8 T cells peaked within the first month after the appearance of symptoms. The frequencies then declined to levels similar to those in latently infected CMV carriers. The CD4 T-cell function followed the same pattern, but with lower peak values.
Immunosuppressed renal transplant patients with latent CMV had CMV-specific CD4 cell function similar to healthy controls. The frequencies of CMV-specific CD8 T cells were also comparable, but their function was impaired. When renal transplant recipients were investigated longitudinally, we found that their CMV-specific T cells decreased rapidly after transplantation. Whereas the frequencies and function of CD8 T cells rebounded within 3 months, CD4 T-cell recovery was impaired during the entire first year after transplantation.
Finally, the frequencies and function of CMV-specific T-cells were investigated in children with congenital and postnatal CMV. CMV-specific CD8 T cells could be detected in even the youngest children, suggesting that these cells can develop early in life. In contrast, CMV specific CD4 T cells were low or absent in the youngest children but increased slowly with age.
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Nissinen, A. (Antti). "Humoral immune response to phosphatidylethanol." Doctoral thesis, Oulun yliopisto, 2011. http://urn.fi/urn:isbn:9789514295232.
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Abstract Heavy alcohol consumption places a substantial burden on health all over the world. Metabolites of alcohol evoke alterations that lead to tissue damage in many organs. Phosphatidylethanol (PEth) is a unique phospholipid formed in the cellular membranes during the metabolism of ethanol after alcohol consumption. PEth has attracted special attention as it is postulated to be a reliable marker of long term heavy alcohol consumption. The aims of present study were to investigate the immunogenicity of phosphatidylethanol in mice and to analyze the plasma antibodies binding to phosphatidylethanol in humans. In this study a clear immune response was generated in mice immunized with PEth in human low density lipoprotein (LDL) carrier. Mouse monoclonal IgM antibodies binding specifically to phosphoethyl head group of PEth were generated using hybridoma technology. Since PEth was shown to be immunogenic in mice, plasma was analyzed for the presence of antibodies also in humans. PEth-specific antibodies of IgG, IgA and IgM isotypes in plasma were detected in heavy drinkers of alcohol with or without pancreatitis as well as in the controls. The plasma levels of the antibodies binding to PEth were significantly lower in the study subjects with heavy alcohol use and in this present study sample the low IgA levels to PEth were better indicators of heavy alcohol consumption as compared to the some of the traditional markers of heavy alcohol use. The antibody levels to PEth associated significantly to plasma antibodies binding to malondialdehyde-acetaldehyde adducts that are known to be formed during alcohol metabolism but not to antibodies binding to phosphocholine which is generated by lipid oxidation in humans. In conclusion, this study demonstrates that phosphatidylethanol is immunogenic in mice when using carriers such as human LDL in the immunization process. The binding of the monoclonal antibodies specifically to the PEth head group suggests that it would be feasible to develop a diagnostic immunoassay to PEth. The presence of antibodies binding to PEth in plasma indicates that PEth may be a target of humoral immunity in humansTiivistelmä Runsas alkoholinkulutus aiheuttaa maailmanlaajuisesti merkittäviä terveydellisiä haittoja. Alkoholin aineenvaihduntatuotteet muuttavat kudoksien rakenteita ja aiheuttavat kudosvaurioita. Fosfatidyylietanoli on alkoholin aineenvaihdunnan tuloksena solukalvoilla syntyvä fosfolipidi, jota on tutkittu kahdenkymmenen vuoden ajan lupaavana alkoholin suurkulutuksen merkkiaineena. Tutkimuksen tavoitteena oli selvittää fosfatidyylietanolin immunisoinnin aiheuttamaa vasta-aineiden muodostumista koe-eläinmallina käytetyissä hiirissä sekä määrittää ihmisten plasmanäytteistä vasta-aineita, jotka sitoutuvat fosfatidyylietanoliin. Tutkimuksessa havaittiin immuunivasteen muodostuminen hiirissä, jotka immunisoitiin ihmisen LDL hiukkasiin liitetyllä fosfatidyylietanolilla. Hiiren monoklonaalisia fosfatidyylietanoliin sitoutuvia IgM-luokan vasta-aineita tuotettiin tutkimuksessa soluviljelyn avulla. Fosfatidyylietanolin aiheuttama vasta-aineiden muodostuminen hiirillä johdatti mittaamaan fosfatidyylietanoliin sitoutuvia vasta-aineita myös ihmisiltä. Tutkimuksessa havaittiin fosfatidyylietanoliin sitoutuvia IgG-, IgA- ja IgM-luokan vasta-aineita alkoholin suurkuluttajilla, alkoholihaimatulehdusta sairastavilla ja verrokkihenkilöillä. Vasta-aineiden pitoisuudet olivat alkoholia runsaasti käyttävillä koehenkilöillä merkitsevästi pienemmät kuin verrokkiryhmällä. Matalat IgA-vasta-ainepitoisuudet osoittautuivat aineistossa paremmaksi alkoholin suurkulutuksen osoittajiksi kuin eräät tavanomaisesti käytetyt alkoholinkäytön merkkiaineet. Plasman fosfatidyylietanoli-vasta-aineiden ja alkoholin aineenvaihdunnan seurauksena syntyvien malondialdehydi-asetaldehydi-addukteihin sitoutuvien vasta-aineiden määrän välillä havaittiin merkitsevä yhteys, jota ei havaittu rasvojen hapettumisen seurauksena syntyvien fosfokoliini-vasta-aineiden ja fosfatidyylietanoli-vasta-aineiden välillä. Tutkimus osoittaa, että hiirillä voidaan aikaansaada vasta-ainevälitteinen immuunivaste, kun ne rokotetaan ihmisen LDL-hiukkaseen liitetyllä fosfatidyylietanolilla. Fosfatidyylietanoliin spesifisesti sitoutuvien monoklonaalisten vasta-aineiden tuottaminen voi tulevaisuudessa johtaa immunologisen diagnostisen määritysmenetelmän kehittämiseen. Fosfatidyylietanoliin sitoutuvien plasman vasta-aineiden havaitseminen viittaa siihen, että fosfatidyylietanoli on vasta-ainevälitteisen immuunivasteen kohde myös ihmisillä
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Lundgren, Christian. "Immune responses in urogenital cancer." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-269894.
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Degabriele, Robert, University of Western Sydney, and of Informatics Science and Technology Faculty. "Stress and the immune network." THESIS_FIST_XXX_Degabriele_R.xml, 1999. http://handle.uws.edu.au:8081/1959.7/406.
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The clonal selection/defence paradigm appears unable to reconcile immune function with homeostatic activity whereas organismic homeostasis is central to immune function in the network/autopoiesis paradigm. The aim of this investigation, therefore, was to test the proposition that immune function, that is not clonally driven (central immune system activity), contributes to organismic homeostasis in collaboration with psychoneural responses. In one experiment sheep were confined, either in groups or individually, and the time course of changes in cortisol levels, behaviour and T lymphocyte numbers were monitored. In another study, soldiers were monitored during the stressful experience of recruit training. The combined results suggest that, at least when the immune response is not clonally driven, the psychoneural system and the central immune system may not be operating independently of each other but rather as sub-networks of the organismic network. Consequently, homeostasis is properly characterised as a property of the whole organism. In autopoietic terms, then, homeostasis could be defined as the maintenance of network stability.Doctor of Philosophy (PhD)
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Chan, Erwin Pai Hsiung. "Immune reactivity to metal implants." University of Western Australia. School of Anatomy and Human Biology, 2009. http://theses.library.uwa.edu.au/adt-WU2009.0194.
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The use of metals like titanium (Ti) and vanadium (V) are common in many medical implants for orthopaedic and orthodontic purposes. The most frequent cause of implant failure is aseptic loosening, resulting from an inflammatory reaction and increased osteolysis at the bone-metal interface. Currently, the pathophysiological mechanism of aseptic loosening remains poorly understood. One hypothesis suggests the reactivity of immune cells (metal hypersensitivity) towards metal ions released through the biocorrosion of metal implants. This thesis examines the effects of titanium and vanadium ions on various immune cells like monocytes, dendritic cells (DCs) and T-lymphocytes. Thereby investigating the role and mechanism which titanium and vanadium plays in aseptic loosening. Through energy filtered transmission electron microscopy, the accumulation of titanium ions was visualized in human monocyte-derived DCs and T-lymphocytes after 24 hours exposure. Titanium was seen to co-localise with phosphorous-rich regions, like the cell membrane, organelles and nucleus of these cells. Flow cytometry measured changes in the cell surface marker expression of monocytes, osteoclasts, DCs and T-lymphocytes treated with the metals. Monocytes exposed to titanium (IV) showed an increase of Tartate-Resistant Acid Phosphatase (TRAP), important for osteolysis and indicative of differentiation towards an osteoclast-like phenotype. DCs treated with Ti(IV) and vanadium (III) had reduced antigen presenting MHC class II expression, but not a reduced capacity to proliferate non-adherent peripheral blood monocytic cells (naPBMCs). Under the influence of Ti(IV), T-lymphocytes, DCs and monocytes expressed elevated levels of the chemokine receptor, CCR4. This would allow for the migration of CCR4+ cells towards the bone and skin regions. Functional changes were measured with BrdU incorporation proliferation assays, cytokine assays (CBA Kits) and the successful generation of titanium-specific T-lymphocytes from Ti(IV) treated DCs. Ti(IV) specific T-lymphocytes conceptually shows the possible formation of an antigenic titanium-protein complex, which can be recognized by the immune system. DCs treated with Ti(IV) and V(III) were able to cause the proliferation of naPBMCs, even with a reduced antigen presenting capability. However, there was no additional influence of V(III) on the immune response through DCs. Cytokines released by DCs and T-lymphocytes after Ti(IV) treatments showed a skew towards an inflammatory Th1-type response through the release of TGF-! and IL-12p70. Activated T-lymphocytes exposed to Ti(IV) also released RANK-L, which drives osteoclastogenesis and subsequently increased osteolysis. The research supports and suggests an interaction between immune and bone cells where titanium-induced inflammation drives an osteolytic cycle that prevents the integration of metal implants into the bone. Hence, suggesting a mechanism for implant failure through aseptic loosening in patients with titanium-vanadium implants.
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Odeberg, Jenny. "Human cytomegalovirus immune evasion strategies /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-126-8.
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Rentenaar, Robert Jan. "Immune responsiveness in immunosuppressed patients." [Amsterdam : Amsterdam : Thela Thesis] ; Universiteit van Amsterdam [Host], 2001. http://dare.uva.nl/document/59814.
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Lidehäll, Anna Karin. "Cellular immune responses to cytomegalovirus /." Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8578.
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Shbat, Layla. "Immune modulation in cardiovascular disease." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103617.
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The importance of the adaptive immune response in cardiovascular disease has been increasingly appreciated. However, limited information is available on immune modulation in the context of hypertension and atherosclerosis. In order to fill this knowledge gap, the amount of T regulatory (Treg) cells was determined by flow cytometry on cells from the spleen and the aorta in two murine models, namely angiotensin (Ang) II-induced hypertension (HT) and endothelin-1 (ET-1)-exacerbated high fat diet (HFD)-induced atherosclerosis in apolipoprotein E knockout (apoE-/-). Two groups of mice were studied. In the first study, 12-week old male C57BL/6 mice were infused with Ang II (1 µg/kg/min, s.c.) for 14 days via an osmotic pump or implanted with a dummy pump. In the second study, 8-week old C57BL/6 male transgenic mice with endothelium-restricted preproendothelin-1 (eET-1) overexpression, apoE-/-, eET-1/apoE-/- crosses, and wild type (WT) mice were fed a HFD or a normal diet (ND) for 8 weeks. A trend towards an increase in several T lymphocyte subpopulations including natural (CD4+CD25+Foxp3+) Tregs was observed in the spleen of mice infused with Ang II whereas in aorta natural Tregs tended to decrease. In atherosclerosis, an increase in classical (CD4+CD25+) Tregs was observed in the spleen of eET-1. HFD reduced the Treg content in the spleen of both WT and eET-1. In addition, HFD tended to increase natural Tregs in eET-1/apoE-/- crosses. In aorta, HFD increased classical Tregs and tended to increase natural Tregs in eET-1 whereas it tended to decrease natural Tregs in eET-1/apoE-/- crosses. The lack of significant change in the above studies limits drawing conclusions. However, the results suggest that ET-1 and HFD have an impact on Treg populations in the spleen and aorta. Additional animals and/or refinement in the techniques could lead to more definitive conclusions.Le rôle de la réponse immunitaire adaptative dans l'hypertension et l'athérosclérose commence à être apprécié. Cependant, il n'est pas clair que les lymphocytes T régulateurs (Tregs) jouent un rôle dans ces deux pathologies. Dans le but d'éclaircir le rôle de ces lymphocytes, le contenu en Tregs a été déterminé à l'aide de cytométrie de flux dans la rate et l'aorte de deux modèles murins, l'hypertension induite par l'angiotensine (Ang) II et l'athérosclérose induite par une diète riche en gras (DRG) dans des souris knockout pour l'apolipoprotéine E (apoE-/-) exagérée par la surexpression de l'endothéline (ET)-1. Deux groupes de souris ont été étudiés. Dans le premier groupe, des souris mâles C57BL/6 de 12 semaines ont été infusées ou pas avec de l'Ang II (1 µg/kg/min, s.c.) pendant 2 semaines. Dans le second groupe, des souris mâles C57BL/6 de 8 semaines transgéniques surexprimant l'ET-1 dans les cellules endothéliales (eET-1), apoE-/-, eET-1/apoE-/- et sauvages (WT) ont été nourries avec une DRG ou une diète normale (DN) pendant 8 semaines. Les souris infusées avec l'Ang II présentaient une tendance à l'augmentation de plusieurs sous-populations de lymphocytes T incluant les Tregs naturels (CD4+CD25+Foxp3+) dans la rate. Par contre, au niveau de l'aorte les Tregs naturels tendaient à diminuer. Dans l'étude de l'athérosclérose, une augmentation des Tregs (CD4+CD25+) a été observée dans la rate des souris eET-1. La DRG a réduit le contenu de Tregs dans la rate des souris WT et eET-1 et tendait à accroître les Tregs naturels dans la rate des eET-1/apoE-/-. Au niveau de l'aorte, la DRG a augmenté les Tregs et tendait à accroître les Tregs naturels dans les eET-1 et tendait à diminuer ces lymphocytes dans les eET-1/apoE-/-. Le manque de changements significatifs limite la possibilité de tirer des conclusions. Cependant, les résultats suggèrent que l'ET-1 et la DRG ont un impact sur la population de Tregs dans la rate et l'aorte. Des animaux additionnels et/ou un raffinement des techniques pourraient donner des résultats plus définitifs.
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Furze, Rebecca Claire. "Immune responsiveness in Trichinella infection." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424923.
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Baker, Richard James. "Human immune responses to alloantigens." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248200.
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Salama, Alan David. "Immune regulation in renal disease." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271077.
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Tan, Lee Aun. "Immune system interactions with phospholipids." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404272.
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Zaccai, Nathan R. "Structural studies on immune receptors." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393447.
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Mukhopadhyay, Subhankar. "Innate immune activation of macrophages." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414236.
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Vakakis, Emmanouil. "Innate immune responses to Picornaviridae." Thesis, University of Sussex, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.516152.
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Viral infections affect millions of people worldwide and pose a major threat to human health. Therefore efforts to understand the host defences against viruses are timely and useful. There are specific receptors on the host cells such as Pattern Recognition Receptors (PRR), which are capable of sensing infectious viruses and initiate reactions collectively known as innate immune responses by detecting motifs or molecular signatures. These responses include activation of antiviral cytokines and initiation of the adaptive immune response, thus inhibiting virus replication. The main two families of PRR involved in virus recognition are the Toll like receptors and the RIG-1 like receptors (RLRs; also known as RIG-1 like proteins or RNA helicases). This study was aimed to clarify the innate immune responses and recognition pathways of Picornaviridae by the host. Picornaviridae are single-stranded RNA viruses that can infect many tissues and organs and produce a variety of symptoms and illnesses to the host. The results from this study have shown that TLRs and RLRs and more specifically TLR7, TLR8 and MDA5 are involved in the detection of Picornaviridae such as Coxsackievirus A9 (CAV-9) and Human Rhinovirus 6 (HRV6) leading to the activation of antiviral cytokines by the host cells.
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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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De, Oliveira O. L. P. "Immune response to Thy-1." Thesis, Open University, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484410.
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