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1
Hanke, Mark L. "Sympathetic Nervous System Mediated Alterations in the Immunological and Behavioral Effects of Social Defeat". The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1283527905.
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Bell, Michael David. "Factors regulating inflammation in the central nervous system". Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308694.
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Babiker, Adil Abdelgadir. "Prostasome Modulation of Blood Cascade System and Phosphoprotein Reactions with Focus on Prostate Cancer". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5779.
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Hassan-Zahraee, Mina. "Anergy and the human skin immune system". Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=42051.
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An initial study comparing cytokine gene expression in the skin of control vs. anergic patients lacking delayed type hypersensitivity reactivity revealed no difference; but disclosed an apparent absence of detectable CD3+ T cells in the skin of anergic individuals. To assess its significance for anergy, an investigation of the role of skin T cells in DTH-reactive healthy individuals was undertaken. To do so, the phenotypic and functional characteristics of T cells isolated from skin and blood were compared. Analysis by flow cytometry has shown that 74% of skin T cells expressed cell surface HLADR, 66% were positive for the IL-2 receptor CD25, and less than 43% have displayed the VLA integrin $ alpha$4 chain as compared to 28%, 7%, 79% for peripheral blood mononuclear cells respectively. The expression of a cutaneous lymphocyte antigen (CLA) was 61% in the former and 14% in the latter. Functionally, skin T cells failed to proliferate in response to all ligands including IL-2, anti-CD3, lectins and phorbol esters with ionomycin, as well as showed a reduced Ca++ flux to phytohemagglutinin. Skin tissue co-cultured with autochtonous PBL could inhibit its proliferative reaction. Despite their ability to proliferate, lymphocytes from skin were shown to be able to produce IFN$ gamma$ in response to PHA+IL-12 as well as anti-CD3+IL-2. Inhibition by anti-cytokine mAbs revealed that in both instances IL-12 was obligatory for this production. In an additional study it was established that a hitherto uncharacterized subset of T cells in blood which could secrete IFN$ gamma$ consisted of CLA+ cells. This observation established a functional link between these CLA+ skin-seeking T cells and the CLA+ T cells in skin.A major difference between IFN$ gamma$-producing cells from blood and skin was found to be the tempo of synthesis: whereas, PBMC was first detected to contain IFN$ gamma$ 42 hours following activation, lasting for days, skin cells were positive after 2.5 hrs of activation, (or 16x faster) for a duration of only 90 minutes. These kinetics were confirmed using intact skin in culture. Experiments designed to reveal the mechanism of this fast action have shown that mRNA for IFN$ gamma$ is present in unstimulated isolated skin T cells as well as in intact skin, but not in PBMC, and its presence may be attributed to ongoing constitutive transcription. Activation of skin T cells, which has been shown to elicit prompt translation in IFN$ gamma$ synthesis has also been shown, at the same time, to terminate IFN$ gamma$ gene transcription in an apparently selective manner. Accordingly, it can be seen that the amount of IFN$ gamma$ synthesized in skin and the duration of its synthesis is preprogrammed. This mode of regulation may be unique to the skin, and unique for IFN$ gamma.$
The results presented are interpreted to indicate that r cells present in human skin may play an essential role in the DTH response, and provide evidence for "peripheral sensitization", or lymphocyte activation outside organized lymphoid tissue. Because of its speed, it may represent the antigen-specific component of a first line cutaneous host defence system. The absence of such T cells in the skin of anergic patients may indeed be responsible for a lack of DTH reactivity, and its clinical consequences.
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Brown, Heidi Catherine. "Macrophages and the nervous system". Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320118.
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Sefik, Esen. "Individual Microbes Shape Various Parts of the Immune System". Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:23845459.
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The gastrointestinal tract, home to a vast number of bacteria, requires finely-tuned regulatory and effector immune mechanisms to maintain homeostasis and tolerance. In a large-scale screen, we studied the impacts of single microbes on major immune populations, whole intestinal tissue homeostasis and metabolism. Bacteria interacted with the host at multiple levels including cytokine responses, accumulation of various T cells, alterations in composition of mononuclear phagocytes and induction of epithelial cell genes as measured by transcriptome analysis of whole intestinal tissue. Interestingly, taxonomically unrelated bacteria elicited similar immune phenotypes and metabolic effects. A more focused analysis of the induction of regulatory mechanisms revealed a microbiota-dependent, context-specific transcriptional control of Foxp3+ regulatory T cells and of IL17 producing T cells. These facets were both regulated by Rorγ, a transcription factor known for its antagonistic effects on Foxp3. Paradoxically, Rorγ expression induced by bacteria in colonic Foxp3+ regulatory T cells was necessary for function of these cells especially in the context of IL17 and IFNγ-mediated colitis. Overall, this large-scale screen provides a comprehensive study of how individual bacterial species shape many aspects of the host immunity and metabolism, and exemplifies a microbiota-dependent, context-specific mechanism that potentiates function in Foxp3+ regulatory T cells.Medical Sciences
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Babcock, Alicia A. "The innate response to injury in the central nervous system /". Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111817.
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Innate responses in the central nervous system (CNS) provide first-line defense against infection and injury. Microglia and astrocytes may direct leukocyte infiltration to the injured CNS. The signaling mechanisms that orchestrate this response are ill-defined. Innate roles for microglia and astrocytes are supported by reports demonstrating glial expression of Toll-like receptors (TLRs). TLRs recognize conserved pathogen-associated motifs and generate innate immune responses, usually by signaling through the adaptor protein, MyD88. TLRs may also generate innate responses to tissue damage. The data in this thesis implicate TLR2/MyD88 as key mediators of innate response to brain injury in mice. Transection of axons in the entorhinal cortex causes tissue damage analogous to a stab injury at the lesion site, and axonal degeneration distal from the wound, in the denervated, lesion-reactive hippocampus. A significant increase in leukocyte proportions was detected by 3h in the stab-injured entorhinal cortex, but not until 12h in the denervated hippocampus. This identified a window of CNS-directed innate response in the denervated hippocampus, without influence of infiltrating cells. Expression of numerous cytokines and chemokines was induced during this time. Microglia and astrocytes were identified as major sources of the chemokine CCL2. Macrophage infiltration to the stab-injured entorhinal cortex and the denervated hippocampus was dependent on MyD88-dependent CCL2/CCR2 signaling, but not TLR2-signalled response. T cell entry to the denervated hippocampus was regulated by TLR2 signaling and required MyD88-mediated response, whereas T cell recruitment to the stabinjured entorhinal cortex was only partially dependent on MyD88 signaling and did not require TLR2-mediated response. TLR2 signaling also regulated expansion of the hippocampal microglial population 5 days after lesion. Microglia were supplemented by circulating bone marrow-derived precursors, but this occurred predominantly at later times post-injury. No parameter measured was dependent on TLR4. These data identify novel signaling pathways that link glial responses to brain injury with subsequent neuroinflammation.
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Drennan, Michael B. "Mycobacterium tuberculosis and trypanosoma brucei as models for the TLR-dependent activation of the innate immune system". Doctoral thesis, University of Cape Town, 2005. http://hdl.handle.net/11427/3111.
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Kristjánsdóttir, Helga. "The PD-1 pathway and the complement system in systemic lupus erythematosus". Doctoral thesis, Uppsala universitet, Medicinsk genetik, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-107198.
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Autoimmune diseases occur in up to 3-5% of the general population and represent a diverse collection of diseases with regards to clinical manifestations. The unifying factor of autoimmune diseases is tissue and organ damage as a result of an immune response mounted against self-antigens. Systemic lupus erythematosus (SLE) is considered a prototype of human systemic autoimmune diseases. The etiology of SLE is as yet largely unknown, but both epidemiological and genetic data suggest an interplay between numerous and varying genetic and environmental factors. There is compelling evidence for a strong genetic component in SLE. The disease has a high λsibs value and familial clustering is apparent. Multiple susceptibility loci have been identified, some of which are syntenic between humans and mice and some of which overlap with other autoimmune diseases. This thesis is based on analysis of Icelandic multicase SLE families and Swedish SLE patients. Paper I is a study of the association of C4A protein deficiency (C4AQ0) with SLE in the multicase families and shows a significantly increased frequency of C4AQ0 in the families. The genetic basis for C4AQ0 varies and C4AQ0 is found on different MHC haplotypes, pointing to C4AQ0 as an independent risk factor for SLE. Paper II describes the association of low MBL serum levels with SLE in the families and identifies low MBL as risk factor for SLE in families that carry the defect. Low MBL was furthermore found to mediate an additive risk when found in combination with C4AQ0. In paper III cellular expression the PD-1 co-inhibitory receptor on T cells was studied. A polymorphism in the PDCD1 gene, PD-1.3A was previously associated with SLE in the multicase families. The polymorphism is thought to disrupt expression of the gene and may lead to decreased expression of the PD-1 receptor. The study demonstrates lower PD-1 expression in SLE patients and relatives in correlation to the PD-1.3A genotype. Paper IV is a compiled analysis of the SLE families, including PD-1.3A, C4AQ0, low MBL, autoimmune diseases and autoantibody profiles. The study demonstrates clustering of different autoimmune diseases and autoantibodies in families that are heterogenic with regards to the genetic susceptibility factors, PD-1.3A, C4AQ0 and low MBL.
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Doody, Karen. "T cell protein tyrosine phosphatase in immune system development and disease". Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104657.
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The ontogeny of the immune system is orchestrated by a highly organized cell signaling network that ensures the development of multiple hematopoietic lineages and allows them to transduce information from their environment in order to mount appropriate responses to prevent disease. The phosphotyrosine signaling network has developed in higher organisms and is undeniably central to the immune system; alterations in components of this network, such as protein tyrosine phosphatases (PTP), can lead to immunodeficiency, autoimmune disease, and hematopoietic malignancy. The T cell protein tyrosine phosphatase (TC-PTP; gene name PTPN2) is highly expressed in hematopoietic tissues, and is involved in the development of several hematopoietic lineages. This thesis addresses the role of TC-PTP in immune system development and disease through the study of a TC-PTP knockout mouse model system. While TC-PTP contains a highly conserved catalytic PTP motif and shares high homology with its family member PTP1B, I have found that these two PTPs are complementary yet non-redundant during embryogenesis as well as myelopoiesis and T cell lymphopoiesis, and thus TC-PTP has a unique function in these processes. Next, I demonstrate that TC-PTP deficiency in mice leads to severe subchondral bone resorption and synovitis. These manifestations resemble early arthritis, and support recent genome wide association studies that identify SNPs in the PTPN2 locus. Finally, I identify the cell autonomous defect involved in the block of B cell development in TC-PTP-/- mice. B cells lacking TC-PTP have increased basal levels of apoptosis as well as increased sensitivity to DNA damage; in addition, these cells have defective V(D)J recombination, suggesting that the apoptosis in TC-PTP-/- progenitor B cells may arise from sensitivity to V(D)J recombination at this stage of development. Such observations elicit interest to study TC-PTP in leukemia development, therefore I also describe the analysis of TC-PTP expression levels in human B cell acute lymphoblastic leukemia in order to address these questions. The research presented herein provides valuable information on the role of TC-PTP in immune system development as well as its role in human immune disease.L'ontogénie du système immunitaire est assurée par un réseau de signalisation complexe qui permet le développement des lignées cellulaire hématopoïétiques, la traduction d'information provenant de l'environnement de la cellule ainsi que la production d'une réponse prévenant tout apparition d'anormalité. Le réseau de phosphorylation protéique des résidues tyrosines, est présent chez les organismes développés et joue un rôle primordiale au niveau du système immunitaire. Les altérations affectant les membres de ce réseau, incluant les protéines tyrosine phosphatases (PTPs), peuvent mener à une déficience immunitaire, des maladies auto-immunes ainsi que des malignités hématopoïétiques. La PTP des cellules T (TC-PTP, nom de gène PTPN2) est une tyrosine phosphatase ubiquitairement exprimée, mais prédominante dans les tissues hématopoïétiques chez lesquels elle assure une fonction primordiale, particulièrement durant leur croissance. Cette thèse adresse le rôle particulier de TC-PTP dans le développement du système immunitaire et ses maladies en utilisant un modèle de souris knock-out (KO) de cette phosphatase. TC-PTP est reconnue pour son homologie avec la protéine tyrosine phosphatase 1B (PTP1B) et toutes deux possèdent un domaine catalytique similaire qui est conservé chez les PTPs. Malgré ces homologies, j'ai pu démontrer que ces deux PTPs ont des fonctions complémentaires et non redondantes au niveau du développement embryonnaire, de la myélopoïèse et de la lymphopoïèse des cellules T. Ainsi, TC-PTP possède un rôle unique dans les processus précédemment énumérés. Par la suite, j'ai démontré qu'une déficience de TC-PTP chez la souris mène à une résorption osseuse sous-chondrale ainsi qu'une synovite, deux phénotypes ressemblant aux symptômes observés durant les premiers stages de développement de l'arthrite. Ces découvertes supportent de récentes études génomiques associant plusieurs polymorphismes situés dans le locus de PTPN2 à différentes maladies auto-immunes. Finalement, j'ai pu identifier chez la souris TC-PTP-/- le défaut spécifique à la cellule en-soi et non son environnement qui est responsable du blocage observé durant le développement des cellules B. Ces dernières n'exprimant pas TC-PTP ont un niveau basal plus élevé de mort cellulaire ainsi qu'une grande sensibilité au dommage à l'ADN. De plus, ces cellules présentent plusieurs défauts au niveau de leur recombinaison V(D)J. Ainsi, la mort cellulaire observée chez les cellules progénitrices B de la souris TC-PTP-/- pourrait donc être expliquée par une anomalie au niveau de la recombinaison V(D)J durant le développement des lymphocytes. Ces multiples observations liant TC-PTP à la lymphopoïèse des cellules B ont menées à l'étude de l'implication de la protéine dans le développement de la leucémie. Par conséquent, une étude de cette phosphatase chez les patients atteints de la leucémie aïgue lymphoblastique des cellules B ont été entamés et sont adressés dans cette thèse. Le projet de recherche présenté procure d'importantes informations concernant le rôle de TC-PTP dans le développement du système immunitaire ainsi que sa fonction dans les maladies auto-immunes affectant la population.
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Soroush, Fariborz. "A Novel Microfluidic System for Screening Anti-inflammatory Therapeutics". Diss., Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/500666.
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Mechanical EngineeringPh.D.
Inflammation is a crucial physiological protective response of body to infection or injury. However, in pathological conditions such as sepsis or radiation damage, the body may exhibit a strong inflammatory response and cause organ damage. Loss of barrier function and leukocyte dysfunction plays an important role during inflammation (e.g. sepsis, radiation exposure, etc.) and induces tissue injury through release of proteases and oxygen radicals. Currently, pharmacological therapies for inflammatory conditions are supportive and there is an urgent need for specific treatments to effectively target key points in neutrophil-endothelial interaction. Our research team has developed a novel microfluidic system to study the mechanisms by which Protein Kinase C isotype delta (PKCδ) impacts neutrophil-endothelial interactions and its inhibition can protect vascular endothelial integrity and attenuate sepsis-induced tissue damage. This novel system will allow for rational design of next generation therapeutics for treating inflammation. We will utilize our novel biomimetic microfluidic assay (bMFA) to systematically delineate the mechanism by which PKCδ regulates individual steps in neutrophil recruitment to the inflamed/activated endothelium. In Specific Aim 1, we will investigate the impact of PKCδ inhibition on neutrophil interaction with endothelial cells as well as adhesion molecules expression. In Specific Aim 2, we will test the specificity of the PKCδ inhibitor in microcirculation and among different species. In Specific Aim 3, we will investigate the role of PKCδ in crosstalk between neutrophils and endothelial cells and endothelium integrity after high dose X-ray irradiation. Our findings indicate that PKCδ inhibition significantly reduces neutrophil interactions with the endothelium during acute inflammation. Our novel biomimetic microfluidic assay (bMFA) provides a rapid screening system for testing the specific response of novel therapeutics. Moreover, results indicate that in many cases the response of murine cells to inflammatory signals may be a poor predictor of response in human cells. Furthermore, our discoveries indicate a key role for PKCδ regulation of radiation-induced changes in endothelial cell barrier structure and function, expression of several key cell adhesion molecules, neutrophil-endothelial cell interaction and leukocyte migration through the endothelium. Our findings indicate that PKCδ-TAT peptide inhibitor may offer an important approach for treating inflammatory disease and we propose that PKCδ inhibition may serve as a novel medical countermeasure for treating radiation-induced vascular damage. Findings from this study will not only elucidate the mechanisms of action for this novel therapeutic but also provide a roadmap for the rational design of future therapeutics for acute inflammatory diseases. The long-term goal of this work is to establish microfluidic devices as a novel prescreening tool for screening therapeutics to allow for fast and precise prediction of response in human. This allows for efficient design of therapeutics using human cells and tissues, designing proper drug carrier, and planning possible future clinical studies.
Temple University--Theses
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Le, Sage Valerie. "Ligand sensing and signal trasnduction by the two-component system PhoP/PhoQ". Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=95624.
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The Citrobacter rodentium genome sequence contains a phoPQ operonhomologous (~79% identity) to that of S. typhimurium. We report that C. rodentiumPhoQ senses fluctuations in Mg2+ concentrations and acidic pH. Surprisingly, PhoQwas not activated by the presence of AMPs. However, activation by AMPs is observedwhen C. rodentium PhoP/PhoQ was expressed in as. typhimurium background. Weidentified an outer membrane protease of the omptin family that was responsible forinhibiting PhoQ activation by AMPs. In stark contrast to S. typhimurium, which relieson LPS modifications to resist AMPs, our results suggest that C. rodentium promotesresistance through a PhoP/PhoQ-dependent OM protease to inhibit disruption of theouter membrane by AMPs .La séquence du génome de Citrobacter rodentium présente un opéron phoPQ(~79% identité) homologue à celui de S. typhimurium. Nous avons déterminé quePhoQ de C. rodentium perçoit les variations de pH et en Mg2+ du milieu environnant.De manière surprenante, les PAMs ne causent aucune augmentation d'activité dePhoQ. Néeanmoins, lorsque le système PhoP/PhoQ de C. rodentium est exprimé chezS. typhimurium les PAMs activent PhoQ. Nous avons identifié une protéine de lamembrane externe appartenant à la famille des omptin qui est responsable del'inactivité de PhoQ en présence des P AMs. Ces résultats suggèrent que le mécanismede résistance aux PAMs de C. rodentium serait régulé par le système PhoP/PhoQ et une protéase qui empêcherait la destruction de la membrane externe par les P AMs. Cemécanisme de défense est différent de celui du système PhoP/PhoQ de S. typhimuriumqui repose essentiellement sur des modification du LPS .
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Ma, Hoi-tung y 馬凱彤. "Studies on the elements in the innate immune system of the shrimp, Penaeus monodon: from recognition, activationto melanization". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B42841501.
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Ajzensztejn, Daniel. "Harnessing the immune system to reject cancers through genetic modifications of tumour cells". Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:1aafa1f4-ee10-4081-b621-d81b9979d96a.
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The immune system, which defends the body against a wide array of threats, is gaining a growing role in the fight against cancer. For an immunotherapy to be successful, it needs to overcome intrinsically weak tumour-specific immune responses. There are two broad approaches to achieving this goal: targeting the various arms of the immune system or targeting the cancer and its microenvironment. The experiments discussed in this thesis adopt the second approach. Tumours were transduced with a combination of costimulatory molecules: CD48, CD54, CD70 & CD86, the chemokine CX3CL1 and the cytokines: IFNγ, GM-CSF and IL-12. Transduction of costimulatory molecules enhances priming in-vitro and cause tumour rejection and delayed tumour growth in-vivo. This effect is demonstrated with single costimulatory molecules but is more pronounced when multiple costimulatory molecules are transduced. Addition of the cytokines and chemokine enhanced tumour rejection, and also resulted in partial rejection of contralateral parental tumours. Attempts to enhance anti-tumour memory by fusing IL-2 and IL-15 to their respective receptors are also discussed. Work in a human/mouse chimeric PD-1 mouse model shows that transduction of multiple costimulatory molecules is able to overcome intrinsic anti-PD-1 resistance. Radiation is known to result in upregulation of several costimulatory molecules within tumours or their infiltrating dendritic cells. The experiments presented here suggest that radiation therapy may be useful in overcoming anti-PD-1 therapy resistance. In human trials, approximately three quarters of cancers fail to respond to anti-PD-1 therapies. Understanding and potentially overcoming anti-PD-1 therapy resistance is therefore of great interest.
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Hatfield, Rachel Sarah. "Development of a polymeric delivery system for DNA vaccines". Thesis, University of Nottingham, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299706.
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Huo, Jiandong. "System-level analysis of early signalling in T cells". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:dcff1741-bd39-4b5b-a11b-99277d55890d.
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The prevailing view of signal transduction is that it proceeds through the linear relay of information via sequential bimolecular interactions, involving, for example, Src homology (SH) 2 domains. It has been assumed that such interactions are highly selective, i.e. that the affinities of these interactions are several orders of magnitude higher than that for non-specific interactions. However, recent studies have suggested that the difference in affinities between so-called specific and non-specific interactions is not sufficient to support such a proposal. This therefore raises the question of how signalling pathway specificity is generated at all. To address this, we have taken a systems approach by expressing and purifying >90% of the SH2 domains identified in a T cell line using a next-generation sequencing-based transcriptomic analysis, and performed a systematic survey of the interaction of these SH2 domains with a set of potential phosphorylated peptides derived from the key signalling receptors of the T cell (including CD28, CTLA-4, PD-1, ICOS, BTLA, LAT and the CD3 subunits of the TCR complex), using surface plasmon resonance-based binding assays. Our results show that, instead of being highly selective for certain SH2 domains, the T cell-expressed receptors are very cross-reactive, such that each receptor is found to interact with ~50 different SH2 domains on average. In silico analysis based on these results confirms the expectation that affinity itself is not the sole determining factor for receptor specificity. Further exploration of the system using in silico simulations incorporating the absolute concentrations of SH2 domain-containing proteins measured in T cells using a proteomics-based approach, suggests instead that the specificity of SH2 domain recruitment by T-cell receptors is the result of systems effects, with expression levels of the signalling proteins being a major factor. Surprisingly, LCK, the most highly expressed SH2 domain in resting Jurkat, is predicted to dominate the binding of most receptors, suggesting a novel mechanism of Src kinase activation and function.
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Lo, Amanda Susana. "Role of Genes in the Jak-Stat Pathway in the Innate Immune System and Immunosenescence in Drosophila melanogaster". Thesis, University of Maryland, Baltimore County, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10275514.
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For many organisms, the immune system tends to deteriorate with age, leading to higher susceptibility to foreign pathogens. While several biological pathways are associated with immunity, the components of the Janus-kinase-Signal Transducers and Activators of Transcription (JAK-STAT) pathway on immunity at different age groups is unclear. This study explored the knock down effects of the Drosophila JAK-STAT pathway components and a candidate gene, robo3, in blood cells. Assessments of immune function were conducted through bacterial clearance assays and phagocytosis assay at one-week and five-weeks of age. This study suggests that some JAK-STAT pathway components important in other cell types seem to have less of a role in blood cells and immunity.
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Bai, Xue-Feng. "Modulation of experimental T cell autoimmunity in the nervous system with emphasis on nasal tolerance /". Stockholm, 1998. http://diss.kib.ki.se/1998ki/19980116baix.
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Hall, Deborah Jean. "Cytokines and their inhibition within the central nervous system in chronic relasping experimental allergic encephalomyelitis". Thesis, University of York, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238710.
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Alvarez, Contreras Carlos Alberto. "HOST-MICROBIOME INTERACTIONS AND REGULATION OF THE IMMUNE SYSTEM". Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1600446008947681.
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Degabriele, Robert, University of Western Sydney y 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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Fooks, Anthony Richard. "Structure of the measles virus nucleoprotein and its interaction with the immune system". Thesis, Open University, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282638.
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Etling, Michele R. "THE AGING MUCOSAL IMMUNE SYSTEM IN THE INTERLEUKIN-10-DEFICIENT MOUSE". Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1184295867.
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Agoropoulou, Catherine. "CD59 expression in the nervous system and its relevance to demyelination". Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390239.
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Durbin, Michael A. "The effects of an oral furunculosis vaccine on the immune system of rainbow trout (oncorhynchus mykiss, Walbaum)". Thesis, Heriot-Watt University, 1997. http://hdl.handle.net/10399/704.
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Diaz, Yacobazzo Alvaro Juan. "A search for mechanism restricting activation of the host complement system in Echinococcus granulosus". Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361948.
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Levy, Daniel Robert Siegfried. "Exploring the role of Leucine Rich Repeat Kinase 2 within the innate immune system". Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/273736.
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Leucine rich repeat kinase 2 (LRRK2) is a 286 kDa protein expressed in a variety of tissues and cell types, including neuronal tissue and innate immune cells. Mutations in LRRK2 have been linked to inflammatory diseases, most notably Crohn’s disease and Parkinson’s disease. Further to this, LRRK2 expression is induced by innate immune stimuli, and can be phosphorylated by Myd88 directed TLR signalling. Functional experiments were performed using macrophages from WT and LRRK2 knockout mice. Many phenotypes and interactions have been described for LRRK2 in a neuronal or in vitro context; therefore experiments in macrophages were specifically designed to investigate these phenotypes and interactions in an innate immune context. LRRK2 interacts with a range of small GTPase proteins called Rabs, which coordinate and carry out vesicular trafficking, including that of innate immune receptors. Further interactions have been shown with clathrin-mediated endocytic machinery and phagocytic machinery; including cytoskeletal components actin and tubulin. Accordingly, the role of LRRK2 in the expression, membrane localisation, and ligand-induced endocytosis of the innate immune receptors such as TLR4 were assayed. TLR4 plays an important role in immune responses to alpha-synuclein, an immunogenic protein aggregate that accumulates as part of Parkinson’s disease pathology, making it a particularly interesting target for this assay. No effect was shown for LRRK2 on TLR4 expression or receptor mediated endocytosis, so attention was focused upon LRRK2 cytoskeletal interactions. An unclear role of LRRK2 has been described in phagocytosis. Application of LRRK2 KO macrophages in a series of systematic phagocytosis assays was used to demonstrate and clarify that there is no role of LRRK2 in the phagocytosis of simple beads, opsonised material, or complex bacterial targets expressing a range of immunogenic molecules such as LPS. A genome wide approach was applied to further investigate the role of LRRK2 in TLR4 mediated signalling, as well as NOD2 mediated signalling. Comparison of LPS responses between WT and LRRK2 KO genotype macrophages identified a role of LRRK2 in modulating transcription of a range of chemokines and chemokine receptors. This indicates a specific role of LRRK2 in regulating chemotaxis in LPS stimulated cells. Knockout of LRRK2 resulted in a complete reversal of the regulation of the expression of EPAC1, a cAMP inducible protein working in parallel with a previously described LRRK2 interacting protein PKA. EPAC1 acts, at least in part, via Ca2+ signalling. Modulation of signalling through pathways such as Ca2+, Wnt and cAMP appear as a theme in results described in this transcriptomic experiment. A parallel metabolomic approach allowed analysis of ceramide levels in resting and innate immune stimulated macrophages. Ceramides are lipid molecules able to activate the NLRP3 inflammasome, as well as modulate alpha-synuclein pathology via ceramide metabolomic products. In contrast to results described in neuronal tissue, LRRK2 has no effect on ceramide levels in resting macrophages, however stimulation of NOD2 via MDP resulted in a dramatic LRRK2 specific increase in ceramide levels. Together, these results indicate a role of LRRK2 in activated innate immune cells.
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Davies, John Stephen. "Heterochronic Parabiosis Studies of the Aging Immune System". Diss., The University of Arizona, 2016. http://hdl.handle.net/10150/613368.
Texto completoResumen
Parabiosis is the surgical union of two organisms resulting in the development of a single, shared circulatory system. When animals of different ages are conjoined (i.e. heterochronic parabiosis), blood-borne factors from the parabionts can affect the physiology of the other parabiont. This is manifested sometimes by beneficial, rejuvenating impact upon the older animal's tissues and organs (anti-geronic effect), and sometimes by younger animal's tissues regressing and appearing old-like (pro-geronic effect). These effects, and the ability to identify individual factors that could recapitulate pro- and anti-geronic effects, have made heterochronic parabiosis a very attractive approach to studying biology of aging and rejuvenation.cHowever, heterochronic parabiosis has not been widely used to investigate the aged immune system. An important question to be answered is whether the cellular defects involved in the aged immune system are due to intrinsic defects or if they can be rescued by extrinsic factors. Heterochronic parabiosis is ideal to test cellular migration patterns, interrogate the mechanisms driving migration defects that occur with aging, establish if these defects can be rejuvenated and identify molecules that are targets for intervention. Here, we provide evidence of the importance of reducing differences in the background genetics of different C57BL/6 substrains prior to parabiosis. This improvement allowed us to improve survival and confirm robust lymphocyte equilibration across secondary, but not primary, lymphoid tissues. We found no evidence for rejuvenation of the old immune cells, whereas results suggested that adult peripheral lymph nodes (pLN) lost mass and cellularity, potentially indicating the presence of a pro-geronic factor(s) in the old circulation that affects pLN function. Adult and old immune cells were present in equal frequencies in both adult and old secondary lymphoid tissues, indicating that there was no restriction of cellular migration due to the age of the cell or age of the tissue. The propensity of adult immune cells (i.e. large naïve compartment) to occupy lymph nodes and old immune cells (i.e. large memory compartment) to occupy bone marrow was retained following heterochronic parabiosis. Finally, parabiosis separation experiments illuminated the peripheral survival advantage of old T cells over adult T cells. These results highlight the power of heterochronic parabiosis in studying immune aging and provide hypothesis-generating data for future mechanistic studies of peripheral T cell maintenance with aging.
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Lundin, Ann-Sofie. "QUALITY OF TACSI PLATELETS AND THEIR EFFECT ON THROMBOCYTOPENIA PATIENTS". Thesis, Uppsala University, Department of Medical Biochemistry and Microbiology, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-126714.
Texto completoResumen
Conclusion:Medical treatment may have a role in platelet count after transfusion. Since the TACSI platelets passed the quality requirements, and the vast majority of patients platelet count increased after TACSI platelet transfusion, the TACSI platelets will replace the old method to produce platelets at the Uppsala University hospital.
Methods: A new approach that pools 8 buffy coats (TACSI platelets) that were separated into 2 units instead of 4-6 buffy coats pooled to 1 unit was investigated in this study. After the platelets were extracted from the buffy coats their quality was controlled and subsequently the platelet product was evaluated in 96 patients.
Results: The results showed that 80 % of the platelet units passed the European quality requirements. Further, the platelet count was increased in most patients that received TACSI platelets.
Conclusion: Medical treatment may have a role in platelet count after transfusion. Since the TACSI platelets passed the quality requirements, and the vast majority of patients platelet count increased after TACSI platelet transfusion, the TACSI platelets will replace the old method to produce platelets at the Uppsala University hospital.
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Chanouzas, Dimitrios. "Cytomegalovirus modulation of the immune system in ANCA associated vasculitis". Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7344/.
Texto completoResumen
Infection and cardiovascular disease represent the two most important sources of mortality in ANCA associated vasculitis (AAV). Expansions of CD4+CD28null T-cells that are only present in cytomegalovirus (CMV) positive individuals have previously been associated with increased infection and mortality in AAV, and cardiovascular disease in other inflammatory diseases. The work described in this thesis examines the hypothesis that subclinical CMV reactivation in AAV drives the expansion of CD4+CD28null T-cells thereby leading to the observed adverse outcomes. To investigate this, a proof of concept clinical trial of 6 months valaciclovir treatment or no additional therapy was designed and implemented in CMV seropositive AAV patients in remission. Valaciclovir treatment successfully blocked CMV reactivation and in turn this led to a reduction in the proportion of CD4+CD28null T-cells in the treated patients together with favourable changes in other associated CMV induced changes on the immune system. CD4+CD28null T-cells in AAV were identified as Th1, proinflammatory cytotoxic T-cells, able to target endothelial cells and were independently associated with increased arterial stiffness, an established marker of cardiovascular risk. These findings implicate subclinical CMV reactivation as a potentially reversible cause of vascular pathology in inflammatory disease and open novel therapeutic opportunities.
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Roper, Janet. "The influence of vitamin E on the immune system of the rainbow trout (Oncorhynchus mykiss)". Thesis, University of Plymouth, 1997. http://hdl.handle.net/10026.1/2444.
Texto completoResumen
This study took the form of three nutritional trials each examining the effects of vitamin E on various physiological, haematological and immunological functions of the rainbow trout. The preliminary study investigated the effect of feeding three experimental diets with different levels of alpha-tocopherol supplementation (0, 100 and 800 mg kgˉ¹ diet), on growth, health and various factors of the non-specific immune response. Liver alpha-tocopherol levels reflected the dietary intake of the vitamin. The fish fed the diet deficient in alpha-tocopherol showed reduced growth and increased mortality They had pale enlarged livers, their hepatosomatic indices and erythrocyte fragility was significantly higher than both the supplemented groups and haematocrit, total serum protein, globulin and complement activity were all significantly lower. No differences were observed between the tissues of the liver, spleen, kidney and heart of the three groups, however the gills structure of the fish fed the diet deficient in alpha-tocopherol showed marked deterioration. The aim of the second trial was to evaluate the effect of feeding different dietary levels of vitamin E (20, 100, 500 mg kgˉ¹ diet) in conjunction with different qualities of oil (fresh or oxidised). In addition to growth and haematological factors, various parameters of the non specific immune response were again evaluated to assess if the feeding of oxidised oil had any effect on these parameters and if the level of vitamin E in the diet had any modulating effect on any differences induced. Fish fed diets containing the lowest level of vitamin E and those fish fed the intermediate level but prepared with oxidised oil, showed classic vitamin E deficiency symptoms, similar to those seen in the preliminary trial and reduced growth and increased mortalities compared to the other groups. Levels of complement activity, were compromised both by low levels of vitamin E and oxidised oil. This suggested that oxidation of the oil content of fish diets increased the requirement for vitamin E and that a high level of vitamin E supplementation was able to compensate to some extent for the deleterious effects induced by the rancid oil. The third trial investigated the effects of different dietary levels of vitamin E (50, 150 and 750 mg kgˉ¹ diet) and immunisation, on antibody responses and mortalities following challenge with Yersinia ruckeri. In addition the effects of diet and immunisation on serum complement activity and levels were measured using three different assay techniques, two based on standard assays and a novel assay, especially developed for this trial, based on an enzyme linked immunosorbent assay (ELISA) technique. This trial, however, did not present any significant results and no correlation between, the level vitamin E supplementation in the diet and antibody response, resistance to Y. ruckeri infection in rainbow trout, could be established. The studies showed that rainbow trout fed diets deficient in vitamin E were immunologically compromised and showed reduced growth and increased mortalities. There appeared to be a definite trend for enhancement of some immunological functions correlated with increased dietary supplementation with vitamin E but this was not always statistically significant and the benefits of dietary supplementation of vitamin E at levels above those currently
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Reichenbach, Zachary Wilmer. "Modulation of the Endogenous Cannabinoid System to Attenuate Inflammation in Central Nervous System Injury". Diss., Temple University Libraries, 2015. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/253514.
Texto completoResumen
PhysiologyPh.D.
In non-pathological states the central nervous system maintains a degree of immunological privilege. When illness or injury occur, this privilege can be lost and the immune system drives pathology in the brain and spinal cord. More so, resident immune cells, the microglial, act as major effectors of this response. Cerebral ischemia, or stroke, is the fourth leading cause of death in developed nations. After the initial ischemia, the inflammatory response propagates further injury and cell death. Another affliction of the central nervous system, chronic pain and persistent use of the opioid analgesic, morphine, leads to tolerance and ineffectiveness of the drug. Currently, only one in three patients receive adequate pain relief from their pharmacological regiment. This loss of efficacy in morphine is also driven by an inflammatory response. Thus, a way to quell inflammation in both disease states could lead to better treatments for both disorders. The endogenous cannabinoid system has two known receptors, CB1 and CB2. Both of these receptors have been intimately linked to inflammation and the activation or antagonism of the receptors can impart desired outcomes in modulating the immune response. Primarily the CB1 receptor expression is on presynaptic terminals of neurons to modulate neuronal firing. The CB2 receptor's expression predominates on immunological cells including microglial. However, some degree of expression exists with reports of neuronal CB2 receptors and immunological CB1 receptors. This makes pharmacological therapies targeted at both receptors ideal candidates in treating not only stroke and but also preventing the induction of morphine tolerance. In the studies described here, we sought to investigate the role of the endogenous cannabinoid system in both stroke and as a way to prevent the induction of morphine tolerance. The results showed that CB1 -/- CB2 -/- receptor mice were able to maintain greater blood flow during cerebral ischemia. More so, CB1 antagonism in a permanent occlusion of cerebral vessels showed a protective effect independent of the serotonin receptor. Lastly, a CB2 agonist was able to limit the degree of tolerance that developed from chronic morphine therapy and also prevent hyperalgesia in addition to showing a reduction in pro-inflammatory cytokines. Acutely, this same agonist was found to antagonize the morphine receptor but this could be avoided if morphine was administered before the CB2 agonist. In brief, the studies at hand show that the endogenous cannabinoid system can attenuate inflammation in central nervous system injury and shows great promise as a future therapeutic for clinical use.
Temple University--Theses
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Hoyeck, Edward. "The effects of moderate swimming exercise on immune system function in C57 BL/6(B6) mice /". Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33288.
Texto completoResumen
The purpose of this study was to separate acute and chronic effects of moderate exercise on the immune system by analyzing three sets of experimental and control groups; (1) 72 hours, (2) 1 week, (3) 2 weeks post exercise. Mice swam 5 days per week for 3 weeks accumulating a total of 125, 225, and 225 minutes of exercise in weeks 1, 2, and 3, respectively. Moderate swimming exercise did not result in a significant increase in SDH levels (p > 0.05). There was no change in tissue cell responses as measured by mitogen responsiveness, nor in splenic and thymic cell counts in response to the training regimen at any time point (p ≥ 0.05). Total, CD4, CD8, and T cell counts in the lymph nodes were significantly suppressed at 72 hours and 2 weeks post exercise (p ≤ 0.05). It appears that chronic exercise resulted in an increased trafficking of lymphatic cells, which could be interpreted as a sign of heightened immune reactivity.
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Beriotto, Irene. "Optimising the autotransporter system for secretion and display of heterologous proteins on GMMA". Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7652/.
Texto completoResumen
The Pet Autotransporter protein was engineered and recently proposed as recombinant protein production (RPP) system. This system allows targeting the protein of interest in the culture supernatant fraction. The reduction of diversity and quantity of process impurities and size and number of downstream steps required, increase the overall process robustness and speed-up the process development time for RPP. In the context of this study the platform was investigated for the production of a “difficult” E.coli protein with commercial relevance, C1275. Pet autotransporter was suitable for the production and one step-purification of a protein with comparable purity, thermal stability and immunogenicity to that produced using conventional technology. Additionally, the autotransporter platform was tested for the first time in scaled-up production conditions. The system was compatible with fermentation and the scaled-up conditions resulted in high yield of antigen production even though a further system optimization would be required for a one step-purification process.
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Goldstone, Robert J. "Investigating the relationship between quorum sensing, motility, and the type 3 secretion system of Yersinia pseudotuberculosis". Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/12471/.
Texto completoResumen
Over the course of the last two decades, research into the role of quorum sensing (QS) in regulating diverse bacterial behaviours has exploded, and around twelve years ago, a QS network was identified in the enteropathogenic bacterium Yersinia pseudotuberculosis, which was shown to control motility and cellular clumping. This thesis seeks to expand this regulatory relationship and explore the causes and consequences of the link between QS and motility, which affects pleiotropic processes including the type 3 secretion system (T3SS) and biofilm formation. Indeed, the clumping phenotype first explored by Atkinson et al. (1999), is linked to QS-dependent regulation of the T3SS, since the deletion of several QS genes results in liquid culture biofilm (LCB) formation. This is concomitant with T3S protein secretion into culture supernatant, which occurs under normally non-inducing conditions, while deleting the T3SS structural component yscJ prevents secretion and LCB formation. De-repression of the T3SS and the development of LCBs also occurs following mutation of the flagella regulators flhDC and fliA, revealing that QS and the flagella system co-regulate LCBs. However, interestingly it was found that LCB formation and secretion also occurs following mutation of the flagella structural gene flhA. The ΔflhA mutant represents a flagella-minus strain, in which the underlying regulatory circuit mediated by FlhDC and FliA is intact, suggesting that an element of the flagella structure that depends on FlhA activity acts as a check-point governing expression of the T3SS. Both QS and the flagella system positively regulate biofilm formation by Y. pseudotuberculosis on the surface of the nematode worm, Caenorhabditis elegans. Surprisingly, the up-regulated T3SS was found to be responsible for mediating down-regulation of biofilm formation by Y. pseudotuberculosis QS mutants, since subsequent deletion of yscJ could restore biofilms to wild-type levels. This suggested that a component of the injectisome was capable of influencing cellular processes in addition to its role in secretion. In light of the link regulatory link between flagella and T3S, this raised the possibility that the injectisome could play a role in the reciprocal regulation of motility. Since the genetic regulatory network underpinning expression of the T3SS is intact in the ΔyscJ mutant, like the ΔflhA mutant for flagella, the ΔyscJ mutant can reveal the role of the injectisome structure in modulating gene expression. By phenotypic observation, it was determined that the ΔyscJ mutant displayed aberrant flagella mediated motility, swimming vigorously under conditions in which the wild-type did not, and, similar to the over-production of Yop proteins in the ΔflhA mutant, the ΔyscJ mutant over-produces flagellin. This suggests that a component of the T3SS injectisome acts as a checkpoint to regulate motility, which appears to be at the level of transcription, since the ΔyscJ mutant displays up-regulation of the flagella regulators flhDC and fliA. Indeed, the relationship between T3S and motility appears to require a direct influence on QS, since subsequent mutation of ypsI and ytbI abolishes ΔyscJ-dependent hyper-motility, the ΔyscJ mutant displays altered expression of the QS system genes. Furthermore, for the emerging transcriptional relationship between these systems, the flagella and QS mutants which are up-regulated for the production of Yop proteins also over-express the virulence regulator virF, completing the transcriptional regulatory circuit which appears to be crucial for the regulation of lifestyle choices by Y. pseudotuberculosis.
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Hung, Hau Yee. "Characterization of the CD4+CD25+regulatory T cells in an animal model of spontaneous demyelination in the central nervous system". Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=66868.
Texto completoResumen
CD4+ T cells have been suggested to play an immunoregulatory role in a transgenic mouse model of CD8+ T cell-mediated CNS demyelinating disease. Among the various CD4+ regulatory T cells, we characterized the CD4+ CD25+ Foxp3+ T cell subset to investigate its potential involvement in regulating disease development in these mice. Our results indicated that in their peripheral lymphoid organs, this population is expanded. This expansion is unrelated to autoimmunity and is not due to an increased thymic generation. Instead, these cells have undergone polyclonal expansion. Furthermore, they harbor typical Treg phenotypes and are in an activated status, but yet display significantly impaired suppressive activities against CD4+ and CD8+ T cell response in vitro. Therefore, this population may not be the regulatory CD4+ T cell subset that controls disease development in this model, and these results challenge the dogma that Foxp3 expression in mice is always associated with suppressive activities.Il a été suggéré que les lymphocytes T CD4+ contrôlent le développement d'une maladie de démyélinisation du système nerveux central, causée par des cellules T CD8+ pathogéniques, dans un modèle de souris transgéniques. Parmi les différentes sous-populations de lymphocytes T CD4+ régulatrices, on a caractérisé la sous-population de cellules T CD4+ CD25+ Foxp3+ dans ce modèle transgénique pour étudier leur rôle potentiel dans la régulation de la maladie. Notre étude démontre que cette population est augmentée dans les organes lymphoïdes de ces souris. Cette augmentation est indépendante de la maladie et elle n'est pas due à une génération augmentée de ces cellules dans le thymus. Par contre, cette population a subi une expansion polyclonale. De plus, elle présente un phénotype typique des Treg, et elle manifeste un état d'activation. Cependant, elle possède un potentiel de suppression des réponses cellulaires T diminué in vitro. Ces données soulèvent le rôle de ces cellules régulatrices in vivo et le dogme que l'expression du Foxp3, dans la souris, est inconditionnellement associée aux activités suppressives.
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Ingram, Justin Phillip. "The Role of the Innate Immune System in Programmed Cell Death". Diss., Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/516594.
Texto completoResumen
Biomedical SciencesPh.D.
Infectious diseases are the leading cause of illness worldwide, leading to over 20 million hospitalizations each year in the United States alone. Although numerous diseases are treatable with vaccines and pharmacological agents, including antibiotics, a large fraction of infections remain poorly controlled, mainly due to lack of effective therapies and/or vaccines. Two such infectious agents are influenza A virus and the bacterium Salmonella enterica. Influenza A virus is transmitted through the aerosol route and infects lung epithelial cells, while Salmonella is transmitted via the fecal-oral route and infects the cells lining the intestine of the host. In each case, the first lines of defense against these infectious agents are non-phagocytic cells. How these pathogens are controlled in non-phagocytic cells dictates the overall outcome of infection; however there are significant gaps in our knowledge of how non-phagocytic cells respond to influenza A virus and Salmonella. Therefore, studying the fate of these cells during the course of infection is of crucial importance to disease outcome. In each case, the regulated (or programmed) death of the infected cell may represent an important pathogen clearance mechanism. Programmed cell death can be non-inflammatory (e.g., apoptosis) or pro-inflammatory (e.g., necroptosis and pyroptosis). In this dissertation, I outline experiments carried out to identify the pathways of programmed cell death activated by Salmonella and influenza A virus in their respective target non-phagocytic cells, both in vitro and in vivo. My work outlines new pathways of cell death activated by these pathogens and new mechanisms of both viral and bacterial clearance. This will have broad implications in the clearance of pathogens, and new therapeutic avenues to pursue upon treating infections.
Temple University--Theses
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Ji, Jie. "Targeting the innate immune system to develop novel prophylactic strategies: lessons from amphioxus (B. lanceolatum) and zebrafish (D. rerio)". Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/525852.
Texto completoResumen
La vacunació és una de les estratègies més efectives de control de les malalties infeccioses. Tot i així hi ha una clara falta de vacunes eficients o d’eines profilàctiques efectives per moltes especies de peixos d’interès comercial. Es necessiten més estudis de recerca bàsica i aplicada per millora la prevenciIBsTNFα) i els liposomes miniaturitzats NLc. Els IBsTNFα són altament estables, no toxics, i són un tipus de biomaterial proteic amb un baix cost de producció. Mitjançant intubació oral de peixos zebra adults i l’ús combinat de citometria, histologia i microscòpia confocal hem demostrat que els IBsTNFα poden atravessar l’epiteli de la mucosa intestinal, passar per la lamina propria i arribar a la capa muscular subjacent. A més l’expressió de gens relacionats amb la resposta innata està significativament regulada a l’alça en intestins de peix zebra. Finalment hem demostrat que els IBsTNFα poden protegir al peix zebra d’una infecció per Mycobacterium marinum. D’altra banda el sistema de nanoliposomes encapsulant LPS i Poly(I:C) o NLc, desenvolupats previament al laboratory, també protegeix al peix zebra contra una infecció letal de M. marinum. També hem explorat la viabilitat d’utilitzar M. marinum i A. hydrophila per desenvolupar un model d’infecció en larves de peix zebra. El model d’infecció de M. marinum no és viable ja que no podem induir mortalitats per inmersió; però el model amb A. hydrophila ha demostrat ser adequat ja que la mortalitat de les larves és depenent de la dosi infective d’A. hydrophila. Els NLc i els IBsTNFαadministrats per inmersió els localitzem a la faringe i l’intestí de les larves de peix zebra a dia 3 i 5 post fertilització. L’expressió de gens de resposta immune es veu regulada a l’alça després del tractament amb NLc. Encanvi no observem una expression a l’alça de gens inmunes després del tractament amb IBsTNFα i això correlaciona amb el fet que els IBsTNFα no protegeixen d’una infecció letal per A. hydrophila.Immunization through vaccination is one of the most effective strategies to control infectious diseases. However, effective vaccines and alternative prophylactic tools for many fish diseases are still lacking. More studies on basic and applied immunology are required to improve the prevention and control of diseases in aquaculture. In this context, the thesis presents both basic and applied research. The Toll-like receptors (TLRs) are important for raising innate immune defense and their ligands are used as vaccine adjuvants to improve the immune responses. We studied the TLR system in the amphioxus B. lanceolatum. We identified 28 new putative TLR genes which consist in both non-vertebrate- and vertebrate-like TLRs. We cloned one of these genes, Bl_TLRj. The phylogenetic analysis together with functional analysis showed that it clusters with TLR11 family and particularly with subfamily 13. Moreover, Bl_TLRj responded against viral stimuli and showed high sequence identity with fish TLR13 and TLR22. Second, we developed two different infection models in zebrafish and we tested two potential nanoparticle adjuvants, IBsTNFα and NLc. The IBsTNFα are a highly stable, non-toxic, and low-cost protein-based biomaterial formed with nano-structured trout tumor necrosis factor alpha cytokine. Via oral intubation of adult zebrafish, combining flow cytometry, histology, and confocal microscopy, we show that IBsTNFα are able to cross the intestinal mucosal epithelial barriers, pass through the lamina propria, and reach the muscle layer. The expression of innate immune-related genes was significantly up-regulated in zebrafish intestine. Finally, IBsTNFα could protect zebrafish against a Mycobacterium marinum lethal infection when i.p. injected. The second particle tested, NLc, was previously developed in our lab and is composed by nanoliposomes encapsulating LPS and Poly I:C. The NLc was tested in our M. marinum bacterial infection model and it could protect zebrafish against a lethal infection when i.p. injected. Next, we explored the infective possibilities of two fish pathogens, M. marinum and Aeromonas hydrophila, in zebrafish larvae by immersion. The mortality of zebrafish larvae immersed with M. marinum showed no significant differences but zebrafish larvae infected with A. hydrophila by immersion showed significant differences compared to controls in a dose-dependent manner. NLc and IBsTNFα localized in the pharynx and intestine of zebrafish larvae at 3 and 5 dpf, respectively. The expression of immune-related genes such as IL-1β and IRF1α was significantly up-regulated after 48 h treatment with NLc in 2 dpf larvae. The 5 dpf larvae immersion in IBsTNFα could not significantly alter immune-related gene expression and IBsTNFα could not protect zebrafish larvae against A. hydrophila lethal infection.
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Feng, Hanping. "Immunological consequences of apoptosis in a tumor system". Diss., The University of Arizona, 2002. http://hdl.handle.net/10150/280040.
Texto completoResumen
Cell lines genetically deficient in caspase-8 have been shown to be resistant to Fas-induced apoptosis, indicating that this pathway may be caspase-8-dependent. Some reports, however, have shown that Fas can induce cell death independent of caspase-8. In this study, we provide evidence for an alternative, caspase-8-independent, Fas death domain-mediated apoptotic pathway in the BCR-ABL positive leukemia cell line, 12B1-D1. Our data suggest that there is a novel, caspase-8-independent, Z-VAD-FMK inhibitable, apoptotic pathway in 12B1-D1 cells that targets mitochondria directly. In attempting to develop effective anti-cancer immunotherapies the relative ability of apoptotic cells to induce an immune response remains an important but controversial consideration. Apoptotic tumor cells can theoretically be a suitable antigen source for stimulation of anti-tumor responses. HSPs can act as danger signals to the immune system. We, therefore, hypothesize that the immunogenicity of apoptotic cell may be enhanced if endogenous HSP expression is induced, or an exogenous source of HSPs is present. To induce endogenous HSPs expression, the engineered 12B1-D1 cells are heat stressed before the induction of apoptosis by AP20187. These stressed apoptotic 12B1-D1 cells express HSP60 and HSP72 on their surface. Vaccination of mice with stressed apoptotic 12B1-D1 cells, but not non-stressed ones, elicits a potent cell-mediated anti-tumor immunity that significantly retards tumor progression. We have further demonstrated that, stressed apoptotic cells had higher abilities to upregulate the co-stimulatory molecules on the surface of DC, to stimulate DC to secrete proinflammatory cytokines, and to enhance their immunostimulatory functions. We further explored whether the immunogenicity of non-stressed apoptotic cell can be enhanced if an exogenous source of HSPs is present at the vaccination site. We used liver derived chaperone proteins co-injected with non-stressed apoptotic tumors to mice. Reproducibly this resulted in the generation of a durable and specific T-cell-mediated anti-tumor immunity. In summary, we have demonstrated that apoptotic tumor cells can be either immunogenic or non-immunogenic and DC may play a key role in determining the immunological consequences of apoptotic tumor cells. We have further demonstrated that normal tissue (liver) MCC may function as a danger signal for the immune system. These may provide new insights for combining immunotherapy with conventional therapies for treatment of cancers.
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Maher, Iona Elizabeth. "Investigations into the effect of koala retrovirus infection on the immune system of koalas". Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/16995.
Texto completoResumen
The aim of this thesis is to investigate the effect of infection with Koala retrovirus (KoRV) on the immune system of koalas. This required the development of real-time RT-PCR assays to measure key cytokines including interleukin 4, interleukin 6, interleukin 10 and interferon gamma and CD4 and CD8β. The response of koala cells to three common mitogen stimulation protocols was assessed and appropriate reference genes (GAPDH and 28s) were validated. These qPCR methods were then used to examine the resting cytokine and CD4:CD8 mRNA expression in Victorian koalas that had either negative, positive or mixed KoRV and Chlamydia infection status. KoRV positive koalas had significantly lower levels of IL17A and IFNγ expression along with a decreased CD4:CD8 compared to negative koalas. qPCR was also used to measure gene expression by mitogen stimulated lymphocytes of koalas infected with a newly discovered variant of KoRV (KoRV B) compared to those without; this was measured four times to control for seasonal variation. KoRV B positive koalas showed significantly increased upregulation of IL17A and IL10 in three out of four sampling periods and IFNγ, IL6, IL4 and TNFα in two out of four. There was also seasonal variation in up-regulation for most cytokines and the CD4:CD8. qPCR was used to detect KoRV A and B from DNA samples from koalas in eight geographically separate populations in NSW. KoRV A was detected in 217/217 of koalas, thus it is likely endogenous in NSW. KoRV B was detected in 21/217 individuals and in all but one population examined in NSW. A pilot study was performed to establish a protocol for incubation of the synthetic peptide CKS-17 (immunosuppressive domain of gamma retroviruses), with mitogen stimulated PBMC’s from KoRV positive and KoRV negative koalas.
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Biesecker, Steven. "THE ROLE OF BACTERIAL AMYLOID FIBRILS IN ESCHERICHIA COLI COMPLEMENT RESISTANCE". Master's thesis, Temple University Libraries, 2012. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/174200.
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Microbiology and ImmunologyM.S.
Strains of Escherichia coli may exist as a beneficial human commensal or a pathogen capable of causing morbidity and mortality. Of the E. coli which causes human disease, many strains which cause bacteremia have been identified as possessing virulence factors which make them more resistant to the complement system. The bacterial amyloid fibril, curli, functions in bacterial adherence and the formation of biofilm. Curli-producing parental and curli-deficient mutant E. coli was compared in its survival to human complement, using in vitro serum sensitivity assays. Results showed an increase in the survival of curli-producing E. coli, which suggested that curli defends against complement killing. An in vivo murine model of E. coli-induced sepsis demonstrated that curli-producing bacteria also survived significantly better in the blood of mice. Immunostaining and flow cytometry was done to determine if parental and mutant strains of E. coli differentially bind to complement components C1q and C3. Results demonstrated that curli increases binding of C1q, but does not affect C3 binding. Blocking the classical pathway suggested that, in these assays, the classical pathway was the major contributor to complement activation and curli inhibits its activity. In addition, blocking the alternative pathway supported that the classical pathway was the main mechanism for complement activation and suggested that curli is not involved in protecting E. coli against alternative pathway activation. Results of this study conclude that curli defends E. coli against complement killing via inhibition of the classical complement pathway.
Temple University--Theses
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Vizel, Mark. "The effect of blood transfusion upon the immune system /". Thesis, McGill University, 1989. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=61951.
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Voice, Marie Ann. "The biology of CD4+ T cells in the blood and central nervous system". Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6210/.
Texto completoResumen
CD4\(^+\) T cells modulate an immune response through the production of effector cytokines. In some circumstances the effector function of CD4\(^+\) T cells is diminished, which may have beneficial (peripheral tolerance) or detrimental (exhaustion, senescence) consequences. Here I characterise a population of CD4\(^+\) cells in human peripheral blood which exhibit complete hyporesponsiveness to in vitro stimulation, as indicated by an absence of CD69 upregulation and the failure to secrete any of thirteen candidate cytokines. These T cells had an effector memory phenotype (CD45RA\(^-\)CCR7\(^-\)\(^/\)\(^+\)CD62L\(^{lo}\)CD27\(^{lo}\)), but their intermediate expression of PD-1 did not suggest a state of exhaustion. Although regulatory T cells (CD25\(^{hi}\)CD127\(^{lo}\)) contributed to the hyporesponsive population it was not predominated by this phenotype. However, the possibility that these hyporesponsive cells represent a non-classical regulatory subset could not be excluded. CD4\(^+\) T cells can enter the central nervous system (CNS) via the blood cerebrospinal fluid barrier, but their biological activity and recruitment pathways are under-defined. Preliminary studies had suggested that hyporesponsive CD4\(^+\) T cells were enriched in uninflamed human cerebrospinal fluid (CSF). However, this investigation found that CSF and brain-derived CD4\(^+\) T cells readily upregulate CD69 upon activation (mouse, human) and have robust IFNγ responses (rat). This evidence supports a role for CD4\(^+\) T cells in CNS immune surveillance and immunity. This investigation also showed that the proportion of CCR7\(^+\) and CCR7\(^-\) memory CD4\(^+\) T cells in the CSF was a direct reflection of the distribution in the peripheral blood in both mouse and man. This suggests that CSF recruitment is not CCR7-dependent as is previously described, and shows effector memory cells enter the CSF space in the absence of neuropathology. Such findings have implications for the understanding of normal immune function in the CNS, and the protective or pathogenic contribution of CD4\(^+\) T cells to neuroinflammatory disorders such as multiple sclerosis.
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Harley, Isaac T. "Modulation of Obesity and its Sequelae by Microbiome/Immune System Interactions". University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1352488859.
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Liu, Pinghuang. "Virus infection and evolution in the central nervous system following intracerebroventricular inoculation with Feline Immunodeficiency Virus". NCSU, 2005. http://www.lib.ncsu.edu/theses/available/etd-10302005-212859/.
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HIV-1 infection of the central nervous system (CNS) results in neurological impairments in subpopulation of HIV-infected individuals which range from from mild cognitive/motor disorder (MCMD) to HIV-associated dementia (HAD). HIV-1 associated neurological diseases are still a big problem even with the introduction of combined antiretroviral therapy. However the mechanisms of CNS infection and pathogenesis that lead to HAD are still not completely clear. HIV-1 CNS infection occurs soon after peripheral infection. Subsequent to infection, the CNS may act as a protected anatomical reservoir for lentiviruses and may also give rise to the development of or sequestration of unique quasispecies. The choroid plexus (ChP) has been demonstrated to be an important site for lentivirus infection and contains a mixture of viral quasispecies including both systemic and brain derived isolates. Since the appearance of viral RNA is particularly prominent in the cerebrospinal fluid (CSF), the ChP-CSF pathway may contribute to infection and viral diversity in the CNS. In the present study, we investigated lentiviral infection and evolution within the CNS by directly infusing virus into the CSF using an FIV animal model. Cell-free NCSU1 FIV or cell-associated FIV (FIV infected ChP macrophages) was directly injected into the right lateral ventricle of the brain. Negative controls were sham inoculated with uninfected ChP macrophages or cell-free culture supernatant and positive controls were infected systemically with cell-free FIV by intraperitoneal (i.p.) injection. Intracerebroventricular (i.c.v.) inoculation with cell-free FIV resulted in high levels of plasma FIV RNA detected as early as 1-2 weeks post inoculation in all 6 i.c.v. cats, and the plasma viremia preceded the detection of CSF viral RNA. Compared to i.p. cats, i.c.v. cats exhibited much higher levels of CSF FIV RNA and FIV DNA in the brain, increased ratios of CSF to plasma viral load (>1 at several time points), and a unique rebound CSF viral peak (5 of 6 cats). Infusion of FIV-infected ChP-Mac induced an acute inflammatory response and a slight suppression of the CD4+:CD8+ ratio, but failed to produce a detectable infection. After cell-free inoculation, FIV env variants, amplified by the poymerase chain reaction (PCR) and isolated using the heteroduplex tracking assay (HTA), exhibited clear compartmentalization between the CNS and periphery. Unique or enriched variants rapidly appeared in the CSF. Similar variation was seen in FIV proviral DNA isolated from cortical and subcortical brain regions. Compared to the initial viral peak in CSF, the second CSF viral peak displayed considerable change from both the first CSF peak and matched samples of plasma. FIV env diversity was highest in the CNS tissue and was unrelated to matched PBMCs collected at the same time indicating that the sequences were not due to PBMC trafficking. In addition, three unique variants were found to be selectively enriched in the CNS. Taken together, these results demonstrated that 1) CSF provides an efficient pathway for the transfer of infectious virus to the periphery, 2) virus trafficking through the CSF promotes infection of the CNS and viral diversification, 3) CSF virus may derive from both the local productive infection and blood, and 4)virus within the CNS experienced a relatively rapid and independent evolution relative to virus in the periphery.
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Joshi, Ayush. "The germinal centre artificial immune system". Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7532/.
Texto completoResumen
This thesis deals with the development and evaluation of the Germinal centre artificial immune system (GC-AIS) which is a novel artificial immune system based on advancements in the understanding of the germinal centre reaction of the immune system. The key research questions addressed in this thesis are: can an artificial immune system (AIS) be designed by taking inspiration from recent developments in immunology to tackle multi-objective optimisation problems? How can we incorporate desirable features of the immune system like diversity, parallelism and memory into this proposed AIS? How does the proposed AIS compare with other state of the art techniques in the field of multi-objective optimisation problems? How can we incorporate the learning component of the immune system into the algorithm and investigate the usefulness of memory in dynamic scenarios? The main contributions of the thesis are: • Understanding the behaviour and performance of the proposed GC-AIS on multiobjective optimisation problems and explaining its benefits and drawbacks, by comparing it with simple baseline and state of the art algorithms. • Improving the performance of GC-AIS by incorporating a popular technique from multi-objective optimisation. By overcoming its weaknesses the capability of the improved variant to compete with the state of the art algorithms is evaluated. • Answering key questions on the usefulness of incorporating memory in GC-AIS in a dynamic scenario.
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Kandeva, Teodora N. 1983. "Humoral response to carbohydrate antigens in the context of ABO-incompatible transplantation and xenotransplantation". Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116121.
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Antibody-mediated rejection is central to ABO incompatible transplantation as well as to xenotransplantation. The xenoantigen alpha-Gal has a highly analogous carbohydrate structure to the human blood group antigens, and both require memory B cell activation for antibody production. We hypothesize that B cells, reactive to the alpha-Gal xenoantigen and B blood group antigen, require the presence of fully activated T cells in order to survive and proliferate in vitro, contrary to the traditional theory that humoral response to carbohydrate antigens is a T cell-independent process. When we compared the capacity of B cells to proliferate, we observed that activated T cells were necessary for B cell proliferation even in the presence of carbohydrate-derived antigens. A relevant question was also to investigate the role of a specific class of T cells: the CD1d-restricted iNKT cells, in the activation of alpha-Gal and B blood group-reactive B cells. The iNKT cells have the specificity of being reactive to glycolipids and are capable of producing both T helper 1 and T helper 2 cytokine responses. We therefore wanted to determine the role of the iNKT cells as mediators of a T helper 2-type response when B cells were exposed to a glycolipid antigen expressing the alpha-Gal epitope or the human B blood group antigen. We observed that, if the interaction between B cells and iNKT cells is blocked, neither B cell proliferation nor antibody production occurs. These results suggest therefore the importance of the iNKT cell category of T helper cells in the response to alpha-Gal and ABO-blood group glycolipids.
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MacDougall, Stephen L. (Stephen Lindsay). "Effector:target interactions in the human natural killer cell system : characterization of the target structures". Thesis, McGill University, 1990. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=74570.
Texto completoResumen
Natural killers (NK) are a subpopulation of lymphocytes that are defined by their pattern of cytotoxicity against other normal and neoplastic cells of predominantly hemopoietic origin. Although they have been programmed to recognize a limited spectrum of targets, their activity can be augmented by certain immunoregulatory substances. The molecules that mediate the recognition events have not yet been identified.I describe here the derivation and characteristics of a variant clone (Clone I) of the human leukemic cell line K562. These cells, selected for decreased binding to peripheral blood lymphocytes, were less sensitive than the parent to lysis by NK in the resting, but not in the augmented state. Although their major plasma membrane proteins appeared identical to those of K562, they contained an additional minor group of fucosylated glycolipids. A later subclone of Clone I, selected for resistance to Concanavalin A, reverted to an NK sensitive pattern and exhibited the parental profile of glycolipids.
The results illustrate in an in vitro model how a leukemic cell can modulate its membrane to escape surveillance by NK cells, and suggest that the glycolipids might be involved (directly or indirectly) in the mechanism.
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Heppolette, Chantal Ann Adele. "The role of early life nutrition in the programming of the adaptive immune system". Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610678.
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Hamad, Osama A. "Crosstalk Between Activated Platelets and the Complement System". Doctoral thesis, Uppsala universitet, Enheten för klinisk immunologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-123681.
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Several studies have shown that complement and thrombotic events co-exist. Platelets have been suspected to act as the bridge between the two cascade systems. To study the platelet-induced complement activation we developed a system in which platelets were activated by thrombin receptor activating peptide (TRAP) in platelet rich plasma (PRP) or whole blood anti-coagulated using the specific thrombin inhibitor, lepirudin. TRAP-activated platelets induced a fluid-phase complement activation measured as generation of C3a and sC5b-9, triggered by released chondroitin sulphate-A (CS-A) which interacted with C1q and activated the complement system through the classical pathway. Complement components C1q, C3, C4 and C9 were also shown to bind to TRAP-activated platelets but this binding did not seem to be due to a complement activation since blocking of complement activation at the C1q or C3 levels did not affect the binding of the complement proteins. The C3 which bound to activated platelets consisted of C3(H2O), indicating that bound C3 was not proteolytically activated. Binding of C1q was partially dependent on CS-A exposure on activated platelets. The abolished complement activation on the surface of activated platelets was suggested to be dependent on the involvement of several complement inhibitors. We confirmed the binding of C1INH and factor H to activated platelets. To this list we have added another potent complement inhibitor, C4BP. The binding of factor H and C4BP was shown to be dependent on exposure of CS-A on activated platelets. The physiological relevance of these reactions was reflected in an elevated expression of CD11b on leukocytes, and increased generation of platelet-leukocyte complexes. The platelets were involved in these events by at least two different mechanisms; generation of C5a which activated leukocytes and binding of C3(H2O)/iC3(H2O), a ligand to the intergrin CD11b/CD18 on their surface. These mechanisms add further to the understanding of how platelets interact with the complement system and will help us to understand the role of the complement system in cardiovascular disease and thrombotic conditions.Platelet Mediated Complement Activation