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1
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.
Повний текст джерелаАнотація:
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.
2
Liu, Yuhong. "Sigma Receptors and the Immune System /." The Ohio State University, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487930304687004.
Повний текст джерела
3
Esplin, Brandt L. "Replenishment of innate immune system in health and disease." Oklahoma City : [s.n.], 2009.
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4
Cho, Sungyoo. "Immune evasion of CD1d molecules and NKT cells in the innate immune response against viruses." [Bloomington, Ind.] : Indiana University, 2005. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:3185405.
Повний текст джерелаАнотація:
Thesis (Ph.D.)--Indiana University, 2005.Source: Dissertation Abstracts International, Volume: 66-08, Section: B, page: 4071. Chair: Randy R. Brutkiewicz. Title from dissertation home page (viewed Oct. 10, 2006).
5
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.
Повний текст джерелаАнотація:
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.
6
Singh, Rekha. "Cellular immune responses in HSV and CMV infections." Thesis, University of Ottawa (Canada), 2003. http://hdl.handle.net/10393/29036.
Повний текст джерелаАнотація:
The herpes simplex virus (HSV) and cytomegalovirus (CMV) are the prominent members of the Herpesviridae family collectively responsible for the majority of herpes-related morbidity and mortality in humans. These viruses are therefore the subjects of this study that was undertaken to improve our understanding of the nature of immune response and the mechanism of viral modulation leading to suppression of viral replication or evasion of the host immune response in vivo.
The present study has examined the T helper responses to HSV-2 and murine CMV (MCMV) and provides new insights into the nature and the modulation of the T helper responses by these viruses in vivo.
B7-1/B7-2 costimulation of T cells by antigen-presenting cells is essential for T cell activation by antigen. HSV-2 infection affects the expression of both B7-1 and B7-2 on monocytes, the key antigen presenting cells in vivo, potentially in two ways with opposing outcomes. It abrogates or diminishes the IFN-gamma-upregulation of B7-1 (in 8 out of 9 patients) and B7-2 (in 6 out of 9 patients) on monocytes. However, the infection also augments the expression of B7-1 and B7-2 on monocytes through an IFN-gamma-independent mechanism (in 9 out of 9 patients). Although the clinical significance of these opposing effects is presently unclear, these may be related to the immunological mechanism or strategy leading to recurrent disease in immunocompetent hosts.
Like HSV-2, infections with MCMV in mice also led to a predominant Thl type immune response characterized by high levels of IFN-gamma and low IL-4 production. Studies with specific MCMV mutants, containing Tn3 transposon in the open reading frame of M25, M27, M43, or m09 gene, led to the identification of M43 gene that specifically suppresses IL-4 response. The Tn3 disruption of M43, but not M25, M27 or m09, gene of MCMV led to a strong IL-4 response (p = 0.0002) despite the presence of a dominant IFN-gamma response. These results provide insight into the possible role of a herpesvirus gene that can profoundly modulate the nature of T helper response in vivo. The presence of a homologous genetic element in other herpesvirus genomes may explain the dominant Th1 immune response triggered by HSV-2 and possibly other herpesviruses. The obvious importance of this finding, beyond herpesvirus immunopathogenesis, lies in the ability of M43 and homologous genes to globally modulate the nature of cytokine response in vivo and suppress Th2 cytokine-mediated diseases. (Abstract shortened by UMI.)
7
Shey, Muki Shehu. "Determinants of innate immune responses to mycobacteria." Doctoral thesis, University of Cape Town, 2012. http://hdl.handle.net/11427/10986.
Повний текст джерелаАнотація:
Includes bibliographical references.Innate cells such as macrophages, monocytes, myeloid dendritic cells and granulocytes recognise mycobacteria and initiate immune responses such as phagocytosis, cytokine production and expression of maturation markers. The type and magnitude of innate responses to mycobacteria may determine the subsequent adaptive responses generated. Our aims were to determine maturational changes in innate immune responses to mycobacteria over the first 9 months of life, and to assess effects of genetic variations in toll-like receptors on host responses to mycobacteria. This knowledge is important for designing rational strategies for vaccination against tuberculosis.
8
Wechsler, Daniel Steven Gary. "Immune mechanisms of cure in Trypanosoma musculi infection." Thesis, McGill University, 1987. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=75348.
Повний текст джерелаАнотація:
Trypanosoma musculi is a protozoan parasite which produces a characteristic, self-limiting murine infection of approximately three weeks duration; the infection comprises a growth phase, a plateau phase and an elimination phase. Following clearance of parasitaemia, a mouse is cured and immune to reinfection. The present studies examine the immune mechanisms which operate during the elimination phase.Passive transfer of plasma from an immune mouse to an infected recipient brings about rapid and complete clearance of parasitaemia in C57BL/6 mice. This curative activity is labile to heat treatment for 30 minutes at 56$ sp circ$C. A protein A- derived immunoglobulin fraction of immune plasma (IP) shares these properties. Further purification shows that the curative activity resides primarily in the IgG2a subclass, and that this antibody is intrinsically heat-labile. Complement component C3 (but not the lytic C5-C9 sequence) is necessary for antibody-mediated cure of infection. Cellular elements (macrophages) are also essential for elimination of parasitaemia to occur. The ultimate T. musculi effector mechanism thus requires the interaction of both humoral and cellular components.
9
Aziz, Douglas C. "Molecular studies on murine acquired immune deficiency syndrome (MAIDS)." Thesis, McGill University, 1990. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=74558.
Повний текст джерелаАнотація:
The Duplan strain of Radiation Leukemia Virus (RadLV) induces an AIDS-like syndrome when injected intraperitoneally into adult C57BL/6 mice. The mice develop T cell depletion, polyclonal B cell proliferation (lymphadenopathy, splenomegaly), hypergammaglobulinemia, and immune deficiency. This syndrome has recently been designated MAIDS (murine acquired immunodeficiency syndrome). This virus preparation, passaged in vivo, is crude and known to contain different strains of retroviruses. To identify the etiologic agent of this disease, we first infected fibroblasts in vitro with this crude virus mixture. Supernatants of these cultures induced disease. Unintegrated viral DNA from fibroblasts newly-infected with this virus preparation was extracted by the Hirt supernatant method and analysed with various viral probes: 8.8 and 4.8 kb DNA species were detected and molecularly cloned in pUC 18 (clones Du9S and Du5H, respectively). An unique DNA sequence derived from the gag region of the defective Du5H genome did not hybridize to various other retroviral DNA's (Moloney MuLV, N-Cl-35 or Du9S). The restriction of Du9S is similar to the map of other RadLV's. The defective Du5H DNA was transfected into fibroblasts in the presence of the neomycin resistance gene and rescued with the non-leukemogenic ecotropic RadLV (G6T2). This virus complex, as well as the ecotropic virus alone, were inoculated into C57BL/6 mice to test their pathogenic potential. The rescued cloned defective virus caused MAIDS, whereas the helper virus (G6T2) alone did not cause disease. Sequence data shows that the defective virus has large deletions in pol and env, and that the gag region is conserved and harbors a novel p12 sequence. This mouse model may help in understanding some important mechanisms underlying the biology of retrovirus-induced immunodeficiency syndromes, such as AIDS.
10
Tran, Elise H. "Immune invasion and glial activation in experimental autoimmune encephalomyelitis." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=36845.
Повний текст джерелаАнотація:
Leukocyte recruitment into tissues in response to infection or injury is a crucial event for the elimination of pathogens to protect the host. However, when leukocytes invade the central nervous system (CNS) and neuromflammatory disorders result, neurological function may be compromised. Infiltration of the CNS, predominantly by T cells and macrophages, characterizes Multiple Sclerosis and its animal counterpart, Experimental Autoimmune Encephalomyelitis (EAE).Autoreactive T cells that initiate EAE produce Th1 cytokines (e.g., IFNgamma, TNFalpha). Nevertheless, previous studies also indicated an unnecessary or even protective role for IFNgamma in EAE. I have identified a novel role for IFNgamma in my studies using IFNgamma- or IFNgammaR-knockout mice. IFNgamma promotes the expression of the chemokines RANTES, MIP-1alpha, and MCP-1, which recruit mononuclear cells in the CNS to induce a non-lethal remitting EAE. Without IFNgamma, the chemokines MIP-2 and TCA-3, and polymorphonuclear leukocytes prevail, producing an unusually lethal EAE. MIP-1alpha is, however, dispensable in recruiting mononuclear cells, as EAE could still be induced in mice deficient in MIP-1alpha or its CCRS receptor.
To examine how much T cells depend on the cooperation with macrophages in the CNS to induce EAE, selective depletion of peripheral macrophages in mice was achieved by intravenous administration of clodronate-loaded liposomes. Treated mice showed no clinical signs of EAE following adoptive transfer of myelin-reactive T cells, but an altered distribution of leukocytes. These leukocytes were confined within the perivascular or meningeal space, not invading the CNS parenchyma. Levels of TNFalpha and inducible nitric oxide synthase (iNOS) in the CNS were reduced in these asymptomatic macrophage-depleted mice compared to untreated mice with EAE. In these asymptomatic mice, NOS expression was restricted to parenchymal astrocytes. In mice with EAE, however, both macrophages/microglia and astrocytes in infiltrates expressed NOS. Surprisingly, some astrocytes that were distant from infiltrates also expressed NOS, thus suggesting that astrocytes may modulate leukocyte infiltration via release of NO through their foot processes in the blood-brain barrier. Collectively, my data propose a model of a dynamic network in which the interplay among cytokines, chemokines and nitric oxide, may determine the magnitude, the composition, or the resolution of inflammatory infiltrates, as well as the clinical outcome of EAE.
11
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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12
Gill, Margaret Elizabeth. "Estuarine fish and their health, as indicators of anthropogenic change." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388651.
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13
Sánchez-Hurtado, Karla. "Pathogenesis of Clostridium difficile and immune response in health and disease." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/25149.
Повний текст джерелаАнотація:
Most patients colonized with C. difficile remain asymptomatic. When C. difficile-associated disease (CDAD) presents, it ranges from mild diarrhoea to severe diarrhoea that can lead to severe complications which can result in colectomy or even death. It is not clear why some patients remain asymptomatic while others present severe disease but one hypothesis is that patients who develop symptoms have lower levels of specific antibodies to C. difficile than those who remain asymptomatic after colonization with C. difficile. The levels of systemic antibodies were analysed in three groups within the elderly hospitalised population of Edinburgh: a) CDAD cases; b) asymptomatic carriers of C. difficile and c) non-colonized controls. Overall, the levels of antibodies were highest in the CDAD cases and lowest in the non-colonized controls suggesting that cases are not unable to mount an adequate response. CDAD cases were more likely to be co-infected with cytomegalovirus (CMV) than asymptomatic carriers or non-colonized controls. CMV might be an indicator of severe disease or might be contributing towards the worsening of CDAD. From the data available, the CDAD cases were more likely to have received β-lactamase inhibitors than asymptomatic carriers, and ciprofloxacin was linked to susceptibility to colonization (but not to disease). The main virulence factors of C. difficile are two exotoxins which are encoded in a region of the genome named “pathogenicity locus” (PaLoc). Real-time PCR was used to investigate if antibiotics affected the expression of the PaLoc genes. The presence of clindamycin induced an increase in the levels of mRNA of the five PaLoc genes wile amoxicillin and vancomycin might help toxin release by creating pores in the C. difficile wall.
14
Xiao, Wenchang. "Structural Health Monitoring and Fault Diagnosis based on Artificial Immune System." Digital WPI, 2012. https://digitalcommons.wpi.edu/etd-theses/169.
Повний текст джерелаАнотація:
This thesis presents a development of Structural Health Monitoring (SHM) and Fault Diagnosis based on Artificial Immune System (AIS), a biology-inspired method motivated from the Biological Immune System (BIS). Using the antigen to model structural health or damage condition of specific characteristics and the antibody to represent an information system or a database that can identify the specific damage pattern, the AIS can detect structural damage and then take action to ensure the structural integrity. In this study the antibodies for SHM were first trained and then tested. The feature space in training includes the natural frequencies and the modal shapes extracted from the simulated structural response data including both free-vibration and seismic response data. The concepts were illustrated for a 2-DOF linear mass-spring-damper system and promising results were obtained. It has shown that the methodology can be effectively used to detect, locate, and assess damage if it occurred. Consistently good results were obtained for both feature spaces of the natural frequencies and the modal shapes extracted from both response data sets. As the only exception, some significant errors were observed in the result for the seismic response data when the second modal shape was used as the feature space. The study has shown great promises of the methodology for structural health monitoring, especially in the case when the measurement data are not sufficient. The work lays a solid foundation for future investigations on the AIS application for large-scale complex structures.
15
Rowsell, Paul. "Oral tolerance and immune mechanisms in food-induced diabetes." Thesis, University of Ottawa (Canada), 1996. http://hdl.handle.net/10393/9599.
Повний текст джерелаАнотація:
Diet controls $\sim$80% of type-I (insulin-dependent) diabetes in the diabetes-prone BioBreeding (BBdp) rat. This study was designed to define the relationship among diet, the gut immune system and the pancreas. BB rats were fed either a diabetogenic NIH-07 (NIH) diet or the diabetes protective, hydrolysed casein (HC) diet. Bovine serum albumin (BSA), ovalbumin (OVA), sheep red blood cells (SRBC) and NIH were given by gavage daily for 5 days. Both BBdp and the diabetes resistant BBc rat when fed NIH became unresponsive in antibody production to NIH antigens. None of the other oral antigen treatments induced tolerance. In delayed-type hypersensitivity (DTH) reactions, footpad injection of NIH resulted in lower DTH reactions and less increase in popliteal lymph node weight when animals were fed NIH than HC. We conclude that oral tolerance, both cell-mediated and humoral, to diabetogenic antigens is inducible in both strains of BB rats. This required daily feeding unlike in other rat strains. The depressed DTH reaction in the animals fed NIH indicates no link between the systemic Th1 DTH reaction to NIH and the Th1 food-induced diabetogenesis. Neonatal intrathymic injection of autoclaved NIH did not affect diabetes incidence, suggesting systemic exposure to these food antigens was not protective. Feeding neonatal BBdp rats a diabetogenic diet between 4 and 7d of age significantly delayed diabetes and reduced incidence. This effect was seen with the NIH diet and its diabetogenic component, wheat gluten. We conclude that early exposure to food diabetogens is protective against food-induced diabetes, indicating a crucial link between the local gut immune system and autoimmunity against pancreatic $\beta$ cells.
16
Sefik, Esen. "Individual Microbes Shape Various Parts of the Immune System." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:23845459.
Повний текст джерелаАнотація:
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
17
Loughhead, Scott McNabb. "Immune Surveillance by Effector and Memory CD8+ T Cells." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:26718721.
Повний текст джерелаАнотація:
During priming, CD8+ T cells integrate a plethora of signals that affect their differentiation into subsets of CD8+ T cells with distinct migratory properties and functions. Given that CD8+ T cells exert their protective function via cell-cell contacts, the migratory patterns and spatial distribution of CD8+ T cell subsets induced by primary challenge are of critical importance to the host. Dendritic cells (DCs), as the primary initiators of these responses, play a pivotal role in shaping the size and differentiation status of CD8+ T cells that emerge. However, inadequate markers for CD8+ T cell subsets have hindered study of their lineage relationships, as well as their migratory behaviors. Here, we use a novel marker for identification of CD8+ T cell subsets to interrogate whether subsets of DCs skew CD8+ T cell fate decisions, the differentiation pattern of CD8+ T cell subsets, and the migratory behavior of these CD8+ T cell subsets.
Within secondary lymphoid organs (SLOs), CD8+ T cells encounter subsets of DCs that may differentially impact subsequent T cell fate decisions. While distinct DC subsets were found to influence CD8+ T cell priming and subsequent differentiation in vitro, these differences were masked when priming occurred in vivo. This prompted us to delve deeper into how CD8+ T cell subsets are defined in vivo. Classically, memory CD8+ T cells are divided into two subsets: central memory T cells (TCM) and effector memory T cells (TEM). Based on the variable expression of the chemokine receptor, CX3CR1, we define TCM as CX3CR1- and TEM as CX3CR1high. Additionally, a previously undefined subset of T cells was identified that express intermediate levels of CX3CR1. Flow cytometric analysis of the subsets migrating through murine peripheral tissues in the memory phase established CX3CR1int cells as the dominant subset, thus these cells have been termed peripheral memory T cells (TPM). Lineage tracing of these three subsets established a uni-directional relationship where increasing levels of CX3CR1 marked further terminal differentiation: TCM (CX3CR1-) to TPM (CX3CR1int) to TEM (CX3CR1hi).
The finding that TPM, and not TEM, migrated through peripheral tissues was intriguing because it contradicted previous studies suggesting that TEM had this migratory pattern. To resolve this contradiction, we visualized the migration of TEM precursors, CX3CR1hi effector T cells (TEff), by intravital multi-photon microscopy (IV-MPM) in real-time. Surprisingly, CX3CR1hi TEff adhered to and patrolled along the dermal endothelium of mice. Specifically, migration was enriched along arteriolar endothelium and tended to be against blood flow. Patrolling occurred for both CX3CR1hi TEff and TEM and was limited to CX3CR1hi CD8+ T cells and CX3CR1hi monocytes, but was not dependent on functional CX3CR1. Moreover, addition of cognate antigen (Ag) resulted in rapid stopping of Ag-specific T cells, suggesting that patrolling T cells scan arteriolar endothelium for cognate Ag. Together, these results challenge the paradigm that TEM function by migration through peripheral tissues and establish a new migratory behavior by TEM and their effector precursors that promotes intravascular scanning of arteriolar endothelium.Medical Sciences
18
Aboalela, Ali Anwar. "Immune Reconstitution of B Cells Following Allogeneic Hematopoietic Cell Transplantation." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17331949.
Повний текст джерелаАнотація:
Objectives: Graft versus host disease (GVHD), infections and disease relapse continue to be major complications of allogeneic hematopoietic cell transplantation (HCT). B cell abnormalities have been associated with these complications, and the objective of these studies was to identify and quantify abnormalities of B cell recovery after allogeneic HCT.
Methods: Flow cytometry was used to analyze peripheral blood from healthy donors (HD) and samples obtained at 1, 2, 3, 6, 9, 12, 18, 24, 30, and 36 months post HCT. A panel of 8 fluorophore-conjugated monoclonal antibodies specific for B cell surface markers was used to identify levels of total B cells, antigen naïve, antigen experienced, transitional B cells, naïve B cells, IgD memory, pre germinal, post germinal, and plasmablasts.
Results: 224 male patients and 175 female patients (total N=399) with a median age of 58 years (range 19-74) were included in this study. 308 patients received reduced intensity and 91 received myeloablative conditioning for allogeneic HCT in the management of various hematological malignancies. The 2-year overall survival was 65% and progression free survival was 55%.
The absolute number of total B cells in patients compared to HD remained low for 9 months (118.8 x 106/L vs 204 x 106/L, P < 0.02) and normal levels were reached by month 12. Recovering cells were primarily antigen naïve B cells and the frequency of antigen experienced B cells remained below normal when compared to HD for all time points post HCT (P < 0.0001).
Within the antigen naïve compartment, the frequency of transitional B cells remained elevated and naïve B cells remained below normal until normal levels were reached by month 9. Within the antigen experienced compartment, the frequency of pre germinal cells was elevated compared to HD from 6 months (4.8% vs 0.70%; P < 0.0002) post HCT. Plasmablast frequencies were elevated compared to HD from 6 months (7.3% vs 1.1%; P < 0.0009) post HCT. IgD memory cells did not reach normal frequency for most time points. Post germinal cells did not reach normal frequencies from 6 to 12 months post HCT.
Conclusion: Disturbances in B cell maturation after HCT persist for prolonged periods despite recovery of normal numbers of circulating B cells. Naïve and transitional B cells that predominate have low affinity BCRs and have been implicated in cGVHD. Reduced numbers of high affinity antigen experienced B cells likely predispose patients to infectious complications post HCT.
19
Verbeke, Catia Stephanie. "Antigen-specific immune modulation using an injectable biomaterial." Thesis, Harvard University, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3627259.
Повний текст джерелаАнотація:
The field of immunology has advanced tremendously over the last 40 years, with seminal findings that have guided the development of powerful new therapies. However, the ability to induce safe and long-lasting antigen-specific tolerance has remained elusive. A therapy that could prevent the immune system from aberrantly destroying self-tissues, without impairing its capacity to eliminate dangerous pathogens, would be transformative for the treatment of autoimmune diseases. In addition, such a therapy could also greatly advance the field of organ transplantation by inducing antigen-specific tolerance to prevent graft rejection.
In this thesis, the overarching goal was to develop a biomaterial delivery system that could recruit and program antigen presenting cells, specifically dendritic cells (DCs), in a non-inflammatory environment, allowing them to orchestrate downstream immune responses that are both antigen-specific and tolerogenic. Gold nanoparticles (AuNPs) were used to deliver a DC recruitment factor, GM-CSF, from an injectable alginate based hydrogel. Both the release of GM-CSF and the physical porous structure of the gel were tuned to achieve effective recruitment of a highly enriched population of DCs. The ability of this system to generate downstream antigen-specific responses in T cells was demonstrated in a mouse model of type 1 diabetes (T1D). Additionally, the DCs recruited in this system were characterized and found to exhibit features that would make them competent to induce tolerance. Finally, a new method was developed for localized delivery and cell-triggered release of a peptide antigen from the material. Over time, antigen-specific T cells expressing FoxP3, a marker of regulatory T cells, which are key mediators of immune tolerance, accumulated in the gels. Together, these findings demonstrate that it is possible to recruit and program DCs in a non-inflammatory context, and that these DCs can induce downstream antigen-specific responses. These promising results suggest that this system may be able to promote tolerance in the setting of autoimmune disease.
This thesis advances the field of immunomodulatory biomaterials by introducing new methodologies for precisely recruiting and manipulating DCs in a non-inflammatory context. This work may provide the basis for further development of a highly effective and therapeutic antigen-specific tolerogenic vaccine.
20
Daftarian, Mohammad Pirouz. "Adverse reactions to sulfamethoxazole in HIV seropositive patients, immune aspects." Thesis, University of Ottawa (Canada), 1993. http://hdl.handle.net/10393/6759.
Повний текст джерелаАнотація:
Adverse reactions to sulfonamides were initially described more than 50 years ago. It is not yet clear whether these side effects are due to immunological reactions or drug toxicity. More than 50% of AIDS patients develop adverse reactions to sulfamethoxazole, a sulfonamide drug commonly used for the treatment of infections in these individuals. In order to study the possible role of the humoral immune response in adverse reactions to SMX in HIV-seropositive patients, I designed an ELISA to determine the classes, subclasses and the quantities of the immunoglobulins directed against SMX. Twenty eight HIV-seropositive individuals with a history of adverse reactions to SMX, 20 HIV-seropositive individuals with no such history, and 39 healthy infants and adults were evaluated for the presence of anti-SMX antibodies. To evaluate the cellular immune response in vitro, lymphocyte proliferation assays were performed in the presence of SMX or structurally related compounds. The lymphocytes from HIV-seropositive patients did not proliferate or produce antibody when incubated with these compounds. Only one immunocompetent individual who had a known hypersensitivity to SMX demonstrated high lymphocyte proliferation to SMX-PLL, but not to structurally related compounds. The mechanism of the development of side effects to SMX is complex, and likely involves both toxic and immunologic events. It may be that high blood levels of SMX may lead to an immune response which produces symptoms only when specific antibody levels have exceeded a certain threshold. The detection of antibodies to SMX may be useful in predicting and managing the adverse reactions to this compound in HIV-seropositive individuals. (Abstract shortened by UMI.)
21
Contreras, Garcia Irazú. "Modulation of the host innate immune response by «Leishmania» parasites." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=95096.
Повний текст джерелаАнотація:
Leishmania parasites have evolved sophisticated mechanisms to subvert macrophage immune responses in order to survive inside the mammalian host. Among these mechanisms are the rapid activation of phosphatases that in turn will inactivate protein kinases and transcription factors, causing abrogation of nitric oxide (NO) production and induction of immunosuppressive molecules. This doctoral thesis discusses novel mechanisms of how the parasite modulates the immune response of macrophages and dendritic cells. Herein, we describe the role of Myeloid Related Proteins (MRPs) 8 and 14 during Leishmania infection. MRPs 8/14 are produced by neutrophils and are able to induce microbicidal activity in macrophages. We present data that shows that priming macrophages with MRP 8/14 before infection induces their activation. However, infection with L. major prior to MRP stimulation significantly decreases their activation. In vivo studies showed that abrogation of MRPs resulted in an increased parasitic burden, whereas injection of recombinant MRPs (rMRPs) reduced the size of the lesion and the parasitic load. One of the main mechanisms that Leishmania parasites utilize to subvert the innate immune response is the alteration of transcription factors (TFs). In this thesis, we have shown that upon Leishmania infection, AP-1 activity is abolished and this correlates with the nuclear degradation of AP-1 subunits. Of interest, c-Jun, the main AP-1 activator is degraded and cleaved by Leishmania inside the nucleus in a GP63 dependent manner. Despite the fact that macrophages have been considered as preferred hosts for Leishmania parasites, other cells have been described as possible hosts. Finally, we discuss the effect of Leishmania infection in dendritic cells (DCs) and how this pathogen affects their maturation and capacity to present antigen. In addition, we found that Leishmania is able to activate phosphatases to inactivate signalling pathways in these cells. Collectively, oLe parasite Leishmania a su développer des mécanismes sophistiqués lui permettant de déjouer les réponses immunitaires des macrophages dans le but de survivre à l'intérieur de son hôte mammifère. Parmi ces mécanismes, notons l'activation rapide de phosphatases, qui inactiveront des protéines kinases et des facteurs de transcription, causant ainsi l'abrogation de la production d'oxyde nitrique, de même que l'induction de molécules immunosuppressives. Cette thèse doctorale discute de nouveaux mécanismes utilisés par le parasite afin de moduler la réponse immunitaire des macrophages et des cellules dendritiques. Dans le présent rapport, nous décrirons le rôle des MRPs (Myeloid Related Proteins) 8 et 14 lors de l'infection par Leishmania. Produites par les neutrophiles, les MRPs 8/14 ont la capacité d'induire l'activité microbicide des macrophages. Nos résultats montrent qu'une sensibilisation active pré-infection des macrophages avec les MRPs 8/14 induit leur activation. Par contre, lorsque l'infection à L.major est antérieure à la stimulation avec les MRPs, l'activation des macrophages est significativement réduite. Les études in vivo démontrent quant à elles que l'abrogation des MRPs a entraîné une augmentation de la charge parasitaire, alors que l'injection de MRPs recombinantes réduit la taille de la lésion, de même que la charge parasitaire. Un des principaux mécanismes qu'utilisent les parasites Leishmania, afin de déjouer la réponse immunitaire innée, est l'altération de facteurs de transcription. À l'aide de nos résultats, nous démontrons que l'activité d'AP-1 est abolie suite à l'infection par Leishmania, ceci concordant avec la dégradation au noyau des protomères d'AP-1. Il est d'ailleurs à souligner que c-Jun, le principal activateur d'AP-1, est dégradé et clivé par Leishmania à l'intérieur du noyau, et ce de façon GP63 dépendante. Malgré le fait que les macrophages sont considérés comme les cell
22
Whitlock, Ben B. "Sigma receptors and the immune system: Identification, localization and functional significance /." The Ohio State University, 1997. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487945744571017.
Повний текст джерела
23
Zhang, Jiachen. "Development of a parameter-insensitive artificial immune system for structural health monitoring." Digital WPI, 2014. https://digitalcommons.wpi.edu/etd-theses/248.
Повний текст джерелаАнотація:
An innovative artificial immune system (AIS) is proposed herein for structural health monitoring (SHM) to ensure the structural integrity and functionality. While satisfactory results were obtained by previous AIS schemes, their performance is strongly structural-parameter-value (SPV) dependent and deviations of SPVs in testing from training due to modeling errors and measurement noises significantly deteriorates the AIS' performance. This thesis presents a less SPV-dependent AIS with a three-phase architecture, including damage-existence-detection, damage-location-determination, and damage-severity-estimation, using specially designed feature vectors (FVs) based on structural modal parameters. The maximum-relative-modal-parameter-change is used to detect the damage's existence and estimate its severity, and the pattern in normalized-modal-parameter-change is used to determinate the damage's location. Comparisons between the proposed FVs and their existing counterparts were conducted for 2/3/4-degree-of-freedom structures to illustrate the superior performance and less SPV-dependence of the proposed method, particularly in determining damage location. The proposed AIS was tested on a 4-degree-of-freedom model using 440 randomly generated damage conditions with a different SPV set per condition. A success rate of 95.23% in the determination of damage's existence and its location was obtained. The trained AIS for the 4-degree-of-freedom model was further evaluated by a four-story and two-bay by two-bay prototype structure used in the benchmark problem proposed by the IASC-ASCE Structural Health Monitoring Task Group. Results have shown great potentials of the proposed approach in its real-world applications.
24
Payne, Caleigh. "The role of prebiotics in dairy calf performance, health, and immune function." Thesis, Kansas State University, 2015. http://hdl.handle.net/2097/20420.
Повний текст джерелаАнотація:
Master of ScienceAnimal Sciences and Industry
Lindsey E. Hulbert
Rapid responses in milk production to changes in dairy cow management, nutrition, and health give producers feedback to help optimize the production and health of dairy cattle. On the contrary, a producer waits up to two years before the investments in calf growth and health are observed thru lactation. Even so, performance, health, and immune status during this time play a large role in subsequent cow production and performance. A recent report from the USDA’s National Animal Health Monitoring System estimated that 7.6 to 8.0% of dairy heifers die prior to weaning and 1.7 to 1.9% die post-weaning (2010). The cost of feed, housing, and management with no return in milk production make for substantial replacement-heifer cost. Therefore, management strategies to improve calf health, performance, and immune function are needed. Prebiotic supplementation has gained interest in recent years as a method to improve gastrointestinal health and immune function in livestock. It has been provided that prebiotic supplementation may be most effective in times of stress or increased pathogen exposure throughout the calf’s lifetime (McGuirk, 2010; Heinrichs et al., 2009; Morrison et al., 2010). Multiple studies have researched the effect of prebiotics around the time of weaning, but to the author’s knowledge, none have focused on prebiotic’s effects during the transition from individual housing prior to weaning to commingled housing post-weaning which may also be a time of stress or increased pathogen exposure. Therefore, a study was conducted to determine the effects of prebiotic supplementation of mannan-oligosaccharide and beta-glucan during this commingling phase. The results indicate that prebiotic supplementation alters feeding behavior, modulates neutrophil function, and increases antibody response during this time. The purpose of industry-based research, such as studies on prebiotics and other methods to improve calf health and performance, is to provide producers with tools to advance and improve their operations. In this respect, it is beneficial to learn what producers’ needs are and what they are interested in improving. An extension survey was conducted to establish priorities, need, and management practices of Kansas dairy producers. The results of the survey indicate that nearly half of the producers (49.3%) are interested in extension programs focused on calf/heifer management. Similarly, over half (54.8%) of the producers responded that they are interested in improving calf/heifer management in the next 5 years. The death loss observed as well as the results of the survey display a need and a producer desire to improve calf management, warranting research on prebiotics and further methods to continue to improve calf health and performance
25
Shank, Alba Maria Montana. "Effects of Stress on Several Immune and Health Responses of Weanling Calves." Thesis, Virginia Tech, 2002. http://hdl.handle.net/10919/34898.
Повний текст джерелаАнотація:
The effects of weaning stressors on several immune and health responses were measured in three experiments. Sixty-four beef calves from 2 sources were bled on d - 7 (pre-weaning), 0 (weaning), 7, 14, and 21 (post-weaning). Serum selenium (Se), neutrophil and lymphocyte counts, and glutathione peroxidase (GSH-Px) activity for erythrocytes and leukocytes were measured for each calf at each date. Erythrocyte GSH-Px activity remained constant over time, while leukocyte GSH-Px and serum Se increased on d 7 (P<0.0001). Effects of single mineral vs. multi-mineral supplementation were measured for several immune and health responses in 2 trials. Trial 1: 36 heifers weaned on-site at SVAREC were randomly assigned 1 of 2 dietary supplements: 1) no supplement; 2) 15% CP at 0.5% BW; and 1 of 3 injection treatments: 1) no treatment (control); 2) Mu-Se injection; 3) Multi-Min injection. Whole blood Se and serum Cu increased post-weaning and serum Zn decreased post-weaning. Mu-Se-supplemented heifers gained weight faster between d 14-28 vs. Multi-Min-supplemented (P=0.01) or control heifers (P=0.02). Trial 2: 48 steers purchased at auction and transported to SVAREC were randomly assigned to 1 of 4 pasture management systems: 1) control (no treatment); 2) litter fed; 3) litter applied; 4) inorganic fertilizer; and 1 of 3 injection treatments (same as Trial 1). Whole blood Se and serum Cu increased post-stress and serum Zn decreased post-stress. Oxidative burst activity decreased in Mu-Se and Multi-min supplemented steers between d 0-4 vs. control steers (P<0.01). Multi-min-supplemented steers had higher phagocytic activity vs. steers in either Mu-Se or control groups (P=0.04).Master of Science
26
Lucas, Robyn Marjorie, and robyn lucas@anu edu au. "Socioeconomic status and health: exploring biological pathways." The Australian National University. National Centre for Epidemiology and Population Health, 2004. http://thesis.anu.edu.au./public/adt-ANU20060426.095241.
Повний текст джерелаАнотація:
The cross-sectional Biomarkers Study was undertaken in Canberra, Australia (2000-2002) to examine the role of psychosocial factors in the socioeconomic health gradient, via physiological changes consequent upon activation of the neuroendocrine
stress response.¶
The study population was derived from healthy 40-44 year old men and women
already participating in a longitudinal cohort study. Using data from the cohort study, four groups with similar occupational status were formed. The study sample was randomly selected within these groups, thus representing the socioeconomic spectrum.¶
A pilot study involved 60 participants with blood and saliva samples measured on two occasions. A further 302 people had blood and saliva samples taken on one occasion. Socioeconomic status was measured by occupational code and status,
personal and household income, education and perceived position in the community and in Australia. Psychosocial and behavioural factors, including job strain, job security, coping style, anxiety, depression, optimism, self-esteem, sense of belonging and trust, social support, smoking, exercise and alcohol intake were assessed by selfreport.
Five biological parameters: plasma fibrinogen, glycated haemoglobin, waisthip ratio, serum neopterin and salivary IgA were measured as outcome variables.Three hypotheses were tested:¶
1. There is a socioeconomic gradient in measures of psychosocial stress, and of
psychological resilience.¶
2. There is a socioeconomic gradient in biological measures that have a plausible¶
association with future disease.
3. Psychosocial factors mediate the demonstrated association between
socioeconomic status and the biological measures.¶
Data analysis confirmed a socioeconomic gradient in some psychosocial and
behavioural variables: economic strain (r=-0.44, p<0.001), job demands (r=0.45,
p<0.001), job control (r=0.26, p<0.001), active coping style (r=0.28, p <0.001), sense
of optimism (r=0.24, p<0.001), social capital (r=0.26, p<0.001), job security (r=0.17,
p=0.002), job marketability (r=-0.16, p=0.005), sense of belonging (r=0.22, p<0.001),
number of adverse life events (r=-0.13, p=0.01) and positive interaction with family
and friends (r=0.20, p<0.001 ), vigorous physical activity (r=-0.16, p=0.002), alcohol
consumption (r=0.30, p<0.001) and smoking status (r=-0.25, p<0.001). There was no
socioeconomic gradient in anxiety, depression, neuroticism, hostility, locus of
control, self-esteem, perceived stress or mental health (SF-12). Four of the five
biological markers varied with socioeconomic status: plasma fibrinogen (female (F):
r=-0.26, p=0.002, male (M) r=-0.08, p=0.30), glycated haemoglobin (F: r=-0.23,
p=0.01, M: r=-0.11, p=0.17), waist-hip ratio (F: r=-0.19, p=0.03, M: r=-0.27,
p<0.001), serum neopterin (F: r=-0.21, p=0.009, M: r=-0.04, p=0.56), salivary IgA
(F: r=-0.07, p=0.38, M: r=0.004, p=0.97). A more adverse biological profile was
associated with lower socioeconomic status. Work characteristics, coping style,
smoking and exercise were particularly important mediators of the association
between the biological markers and socioeconomic status. Particular psychosocial factors were consistent mediators of the association between specific biomarkers and
socioeconomic status (with little variation for different measures of socioeconomic
status). However, the particular psychosocial factors providing significant mediation
varied for the different markers.¶
In this sample of healthy 40-44 year olds, four out of five biological markers showed
moderate socioeconomic variation with a more favourable profile associated with
higher SES. The data provide limited support for the importance of psychosocial
factors in the socioeconomic health gradient.
27
Youniss, Fatma. "MULTI – MODALITY MOLECULAR IMAGING OF ADOPTIVE IMMUNE CELL THERAPY IN BREAST CANCER." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3323.
Повний текст джерелаАнотація:
Cancer treatment by adoptive immune cell therapy (AIT) is a form of immunotherapy that relies on the in vitro activation and/or expansion of immune cells. In this approach, immune cells, particularly CD8+ T lymphocytes, can potentially be harvested from a tumor-bearing patient, then activated and/or expanded in vitro in the presence of cytokines and other growth factors, and then transferred back into the same patient to induce tumor regression. AIT allows the in vitro generation and activation of T-lymphocytes away from the immunosuppressive tumor microenvironment, thereby providing optimum conditions for potent anti-tumor activity. The overall objective of this study is to: a) develop multi-modality (optical- and radionuclide-based) molecular imaging approaches to study the overall kinetics of labeled adoptively transferred T- lymphocytes in vivo, b) to non-invasively image and assess in-vivo, targeting and retention of adoptively transferred labeled T-lymphocytes at the tumor site. T-lymphocytes obtained from draining lymph nodes of 4T1 (murine breast cancer cell) sensitized BALB/C mice were activated in vitro with Bryostatin/ Ionomycin for 18 hours, and were grown in either Interleukin-2 (IL-2) or combination of Interleukin-7 and Interleukin-15 (IL-7/IL-15) for 13 days, (cells grown in IL-2 called IL2 cells, and cells grown in IL7/15 called IL7/15 cells). In order to validate the methodology and to offer future clinical translation, both direct and indirect cell labeling methods were expanded and employed. The first method was based on direct in vitro cell labeling by lipophilic near-infrared (NIR) fluorescent probe, 1,1- dioctadecyltetramethyl indotricarbocyanine iodide, (DiR), followed by intravenous (i.v.) injection into BALB/C mice for multi-spectral fluorescence imaging (MSFI). The second method was based on indirect labeling of T- lymphocytes through transduction of a reporter gene (cell cytoplasm labeling Herpes Simplex Virus type 1- thymidine kinase (HSV-1 tk). The product of this reporter gene is an enzyme (HSV-1TK) which phosphorylates a radio labeled substrate 2-fluoro-2-deoxy-1 β- D- arabinofuranosyl-5-iodouracil ([124I]-FIAU) for Positron Emission tomography (PET) imaging. ATP based cell viability assay, flow cytometry and interferon-γ (IFN-γ) ELISA were used to investigate if there are any changes in cell viability, proliferation and function respectively, before and after direct and indirect labeling. The results showed that cell viability, proliferation, and function of labeled 4T1 specific T-lymphocytes were not affected by labeling for direct labeling methods at DiR concentration of 320µg/ml. For the indirect labeling method, the viability and proliferation results showed that cell viability decreases as multiplicity of infectious (MOI) increases. In particular, at MOI of 10 almost all cells die 3 days post transduction. At MOI of 5, cells viability was ≤ 30% and at MOI of 2 was ≤ 60%. Cell viability was 80% at MOI of 1. The results of optical imaging were as follows: when the recipient mice with established 4T1 tumors were injected with DiR labeled 4T1 specific T-lymphocytes, the 4T1 specific T-lymphocytes (IL2 cells) infused into tumor-bearing mice showed high tumor retention, which peaked 3 or 6 days post infusion depending on the tumor size and persisted at the tumor site for 3 weeks. In contrast, IL7/15 cells showed lower signal at the tumor site and this peaked on day 8. On the other case when 4T1 tumor cells were implanted 1-week post-infusion of labeled T-lymphocytes. IL2 T-lymphocytes moved out of lymphoid compartments to the site of subsequent 4T1 inoculation within two hours and peaked on day 3 and the signal persisted for 2 more weeks. In contrast with infusion of IL7/15 cells, the signal was barely detected and did not show a similar trafficking pattern as with IL2 cells. The results of the indirect labeling method, PET reporter gene (PRG) system (HSV-1tk / [124I ] FIAU ) showed that both IL2 and IL7/15 cells were successfully transduced as verified ex vivo by real time PCR and western blot. T Cells transduction efficiency was assessed from cell uptake study in comparison to stable transduced Jurkat cells which have transduction efficiency of 100 %. Both IL2 and IL7/15 cells showed lower transduction efficiency (≤ 30%) compared to Jurkat cells. Consequently, PET imaging did not show a detectable signal of transduced T cells in vivo. Biodistribution study was carried out on day 3 post [124I]-FIAU injections. Results were consistent with the optical imaging results, except for IL7/15 cells. Transduced and untransduced IL2 and IL7/15 cells were labeled with DiR and injected ( i.v.) into Balb / C mice and then imaged by both imaging modalities (MSFI and PET) at the same time. MSFI images of transduced IL2 cell showed detectable signal starting from 2 hours, peaked at 72 hours and persisted up to 2 weeks, while IL7/15 cells were detectable at the tumor site starting at 24 hours, peaked at 72 hours and persisted up to 2 weeks. By the end of this study animals were dissected and tissue activities were counted using gamma counting and expressed as % Injected dose/gram of tissue (%ID/gm). Transduced IL2 and IL7/15 cells showed higher %ID/gm than other organs at lungs, liver, spleen, tumor, lymph nodes and bone/bone marrow. IL7/15 cells compared to IL2 cells showed higher %ID/gm at same organs. Neither IL2 nor IL7/15 untransduced DiR labeled cells showed any activity at tumor site, and their activities at other organs was very low compared to transduced cells. To investigate whether labeled T-lymphocytes will localize at tumor metastases or not, and to study the difference in their migration patterns to the tumor site versus tumor metastases, 4T1 tumor cells were successfully transduced with HSV-1tk as confirmed by RT-PCR , western blot and cell uptake study. Transduced 4T1 cells were implanted in the right flank or in the mammary fat pad of the mouse. Serial PET imaging was carried out in the third and fourth week post tumor implantation to know when the tumor will metastasizes. PET imaging showed only signal at the tumor site and no metastasis were detected.
28
Malik, Suneil. "Genetics of host innate immune factors in Tuberculosis susceptibility." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85578.
Повний текст джерелаАнотація:
Tuberculosis, caused by Mycobacterium tuberculosis, is globally a leading cause of morbidity and mortality. While a host genetic contribution to tuberculosis susceptibility is known to occur, the extent and nature of host genetic variability to tuberculosis pathogenesis are unknown. Thus, to better understand the role of host genetic factors in tuberculosis susceptibility, we have tested the contribution of candidate gene variants to tuberculosis susceptibility in three geographically, epidemically, and clinically distinct populations. We chose four candidate genes involved in the innate immune response, namely, NRAMP1, MBL, SFTPA1, and SFTPA2.Since the global spread of tuberculosis is highly dependent on HIV/AIDS pandemic, we investigated the association of genetic MBL variants and HIV-1 infection in 278 Colombian HIV-infected and control individuals. MBL genotype frequencies were similar for both groups, and no association was detected between MBL alleles B, C, and D and susceptibility to HIV-1 infection (P = 1.0). These results do not support the hypothesis that MBL levels are a risk factor for HIV-1 infection in Colombia. Moreover, we were able to show that MBL variants do not contribute to tuberculosis susceptibility in this population.
In a pediatric population composed of 184 families we found allelic variants in the NRAMP1 gene to be associated with tuberculosis disease (P = 0.01; Odds ratio [OR] = 1.75 [95% confidence interval: 1.10--2.77]). Common NRAMP1 alleles were identified as risk factors for pediatric tuberculosis while these same alleles were reported to be protective in adult cases, suggesting that the common alleles promote rapid progression from infection to tuberculosis disease. Furthermore, the association of NRAMP1 with pediatric tuberculosis disease was significantly heterogeneous (P = 0.01) between simplex (P < 0.0008; OR = 3.13 [1.54--6.25]) and multiplex families (P = 1) suggesting an interplay between mechanisms of genetic control and exposure intensities. Finally, we tested the correlation between the NRAMP1 risk and NRAMP1 functional activity by measuring the recruitment efficiency of mannose-6-phosphate receptor (M6PR) to Salmonella containing vacuoles (SCV) in monocyte-derived-macrophages (MDM). We show that recruitment of M6PR to SCV is significantly lower ( P = 0.024) in MDM from patients homozygous for the risk allele as compared to MDM from heterozygous patients. Thus, altered function of NRAMP1 appears to modulate the rate of progression from infection to disease.
29
Akin, James. "IAP Inhibitors as Novel Immune Adjuvants for Scaffold Based Cancer Vaccines." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467467.
Повний текст джерелаАнотація:
Inhibitors of apoptosis (IAP) antagonists are nearing approval as promising new candidates for cancer therapy, particularly for solid tumors. Previous work had uncovered the ability of the monomer version of this drug to co-stimulate T cells and enhance anti-tumor immunity when administered systemically in conjunction with B16/GVAX, a model of melanoma immunotherapy. Further published work from multiple labs revealed the ability of these drugs to influence a variety of immune subsets. Given that IAP proteins are known to regulate alternative NFkB downstream of TNFR family members (e.g. GITR, BAFF-R, LTBR), it is evident that IAP antagonism has different effects on non-immune versus immune cells. Where drug treatment in non-immune cells sensitizes these cells to apoptosis, in contrast immune cells do not undergo cell death. We have uncovered the ability of both monomer and dimer inhibitor to enhance survival in B cells cultured ex-vivo and, in the context of stimulation, further costimulate these cells. In an effort to improve the therapeutic effect in our model we investigated local delivery of IAP antagonists via bioabsorbable poly-lactide-co-glycolide (PLG) scaffolds. Interestingly, IAP monomer, but not dimer resulted in reproducible reduction in tumor growth and increased survival of mice when delivered peritumorally in the absence of additional immunotherapy. Further studies in naive mice revealed increased cellular infiltration in monomer loaded scaffolds when compared to blank scaffolds across a month time course. Upon FACS analysis of these cellular infiltrates, scaffolds loaded with drug contained a striking enrichment of B cells and follicular dendritic cells, suggesting IAP inhibitor delivered in subcutaneous site could form tertiary lymphoid structures, an intriguing possibility given that lymphotoxin signaling, essential for secondary lymphoid organ development, occurs through alternative NFkB. Additional ex vivo experiments revealed that monomer, but not dimer could enrich for lymphoid tissue inducer cells, suggesting the possibility that IAP monomer could be used as a novel immune adjuvant delivered locally where it could impact higher order immune interactions as a therapeutic agent by itself.Medical Sciences
30
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.
Повний текст джерелаАнотація:
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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Coulter-Hennekens, Kelsye. "HLA associations with specific immune responses : the Ra5 ragweed allergen model." Thesis, McGill University, 1987. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=75370.
Повний текст джерелаАнотація:
Previous studies have established that sensitivity (IgE antibody response) to Ra5S, a 5 kd protein of short ragweed pollen, is significantly associated with host possession of HLA-Dw2/DR2 (Bias et al., 1979; March et al., 1982a; Coulter, 1983). The present work was undertaken to determine a possible association between HLA and sensitivity to Ra5G, an Ra5S homologue from giant ragweed pollen. The DR2 allele was also implicated in sensitivity to Ra5G, on the basis of co-sensitivity to both proteins (Goodfriend et al., 1985). Further analysis with an enlarged RW allergic population demonstrated that sensitivity to Ra5G and Ra5S is associated with separate alleles: DRw52 and DR2 respectively. Results consistent with the same sensitivity/DR associations were obtained in immunoabsorption studies with sera from co-sensitive individuals. As HLA-DR2 and DRw52 have identical alpha but different beta chains, it was considered that IgE antibody responses to Ra5S and Ra5G are associated with distinct DR-beta genes.
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Rhee, Inmoo. "Roles of protein tyrosine phosphatase PTP-PEST in innate immune cells." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=121296.
Повний текст джерелаАнотація:
PTP-PEST (protein tyrosine phosphatase - proline-, glutamic acid-, serine- and threonine-rich; also named PTPN12) is an intracellular protein tyrosine phosphatase highly expressed in non-immune and immune cells. PTP-PEST was previously reported to be a critical regulator of cytoskeletal reorganization, cell adhesion and migration in non-immune cells. Moreover, PTP-PEST has a role as tumor suppressor in several types of human solid tumors. Recently, the roles of PTP-PEST in immune cells have also been clarified, using a cell type-specific conditional PTP-PEST-deficient mouse. In T cells, PTP-PEST has an essential role in secondary T cell activation, inhibition of T cell anergy and induction of autoimmunity. The data presented in this thesis address the roles of PTP-PEST in innate immune cells, including macrophages and dendritic cells. Macrophages are innate immune cells that efficiently eliminate pathogens, tumor cells and cell debris, largely through phagocytosis and cytokine production. Under special conditions, they can also undergo cell-cell fusion to form multinucleated giant cells and osteoclasts, which have been implicated in elimination of pathogens or foreign bodies and bone resorption, respectively. Using a macrophage-targeted PTP-PEST-deficient mouse, I show that PTP-PEST is a critical positive regulator of macrophage fusion into multinucleated giant cells in response to interleukin-4 (IL-4). Using a macrophage cell line (RAW264.7), I provide evidence that PTP-PEST is also important for macrophage fusion into osteoclasts in response to RANKL (receptor activator of nuclear factor kappa-B ligand). Further studies indicate that the critical role of PTP-PEST in macrophage fusion is due to its involvement in the control of migration and adhesion of macrophages during the fusion process. This function correlates with the ability of PTP-PEST to regulate the extent of tyrosine phosphorylation of the protein tyrosine kinase, Pyk2, and the adaptor molecule, paxillin.Dendritic cells are the most efficient antigen-presenting cells in the body. They are able to capture and process antigens in peripheral tissues. Upon maturation in response to inflammatory stimuli, they then migrate to lymphoid tissues, where they are able to present processed antigens to antigen-specific T cells. This cascade enables initiation of T cell-dependent immune responses. Using a dendritic cell-targeted PTP-PEST-deficient mouse, I observe that PTP-PEST is crucial for the capacity of dendritic cells to initiate T cell-dependent immune responses and immune pathology in vivo. This function is due in part to a minor role of PTP-PEST in antigen capture, processing or both. More significantly, it is also caused by an essential role of PTP-PEST in dendritic cell migration from peripheral tissues to lymphoid tissues. As is the case for macrophages, this activity correlates with the aptitude of PTP-PEST to control tyrosine phosphorylation of Pyk2 and paxillin.Together, the new findings described in this thesis provide strong evidence that PTP-PEST mediates essential functions in innate immune cells.PTP-PEST (protéine tyrosine phosphatase riche en proline, acide glutamique, sérine et thréonine; également connue sous le nom de PTPN12) est une protéine tyrosine phosphatase intracellulaire abondamment exprimée dans les cellules immunes et non immunes. Auparavant, PTP-PEST a été considéré comme un régulateur critique de la réorganisation du cytosquelette, l'adhésion cellulaire et la migration des cellules non immunes. De plus, PTP-PEST a un rôle en tant que suppresseur de tumeurs dans plusieurs types de tumeurs solides humaines. Récemment, les rôles de PTP-PEST dans les cellules immunes ont également été clarifiés en utilisant une souris ayant une déficience conditionnelle de PTP-PEST. Dans les cellules T, PTP-PEST joue un rôle essentiel dans l'activation des réponses secondaires, l'inhibition de l'anergie des cellules T et l'induction de l'auto-immunité. Les résultats présentés dans cette thèse portent sur les rôles de PTP-PEST dans les cellules du système immunitaire inné incluant les macrophages et les cellules dendritiques. Les macrophages sont des cellules du système immunitaire inné qui éliminent de façon efficace, principalement par phagocytose et production de cytokines, les pathogènes, les cellules tumorales et les débris cellulaires. Dans certaines conditions particulières, les macrophages peuvent former, par un processus de fusion intercellulaire, des cellules multinuclées géantes ou des ostéoclastes qui sont, respectivement, impliquées dans l'élimination des pathogènes ou des corps étrangers, et dans la résorption osseuse. À l'aide d'une souris ayant une déficience de PTP-PEST spécifique aux macrophages, nous avons démontré que PTP-PEST est un régulateur positif essentiel pour la formation de cellules multinuclées géantes par la fusion des macrophages en réponse à une stimulation par l'interleukine-4. En utilisant une lignée cellulaire de macrophages (RAW264.7), nous avons également mis en évidence que PTP-PEST est important pour la formation d'ostéoclastes par la fusion des macrophages en réponse à l'activateur RANKL (Receptor Activator of Nuclear factor Kappa-B ligand). Des études plus poussées ont révélé que ce rôle essentiel de PTP-PEST dans la fusion des macrophages dépend de son implication dans le contrôle de la migration et de l'adhésion des macrophages pendant le processus de fusion. Cette fonction est en corrélation avec la capacité de PTP-PEST de contrôler le niveau de phosphorylation sur tyrosine de la protéine tyrosine kinase Pyk2 et de la molécule adaptatrice paxillin.Parmi les cellules présentatrices d'antigène dans le corps, les cellules dendritiques sont les plus efficaces. Elles sont capables de capter et de traiter des antigènes dans les tissus périphériques. Suite à leur maturation en réponse à des stimulations inflammatoires, elles migrent vers les tissus lymphoïdes où elles présentent des antigènes spécifiques aux cellules T appropriées. Cette suite d'événements permet de déclencher les réponses immunitaires dépendant des lymphocytes T. En utilisant une souris ayant une déficience de PTP-PEST spécifique aux cellules dendritiques, nous avons montré que PTP-PEST est crucial pour permettre aux cellules dendritiques d'initier ce type de réponse immunitaire ainsi qu'une pathologie immune in vivo. Cette fonction est due en partie au rôle mineur de PTP-PEST dans la capture ou le traitement des antigènes, ou les deux. Cependant, d'une manière plus significative, cette fonction découle du rôle essentiel de PTP-PEST dans la migration des cellules dendritiques des tissus périphériques vers les tissus lymphoïdes. Comme dans le cas des macrophages, cette activité est en corrélation avec la capacité de PTP-PEST de contrôler la phosphorylation sur tyrosine de Pyk2 et de paxillin.L'ensemble des nouvelles observations décrites dans cette thèse démontre clairement le rôle essentiel de PTP-PEST dans les cellules du système immunitaire inné.
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Laserson, Uri. "High-throughput methods for characterizing the immune repertoire." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/79246.
Повний текст джерелаАнотація:
Thesis (Ph. D. in Biomedical Engineering and Computational Biology)--Harvard-MIT Program in Health Sciences and Technology, February 2013."September 2012." Cataloged from PDF version of thesis.
Includes bibliographical references (p. 147-160).
The adaptive immune system is one of the primary mediators in almost every major human disease, including infections, cancer, autoimmunity, and inflammation-based disorders. It fundamentally functions as a molecular classifier, and stores a memory of its previous exposures. However, until recently, methods to unlock this information or to exploit its power in the form of new therapeutic antibodies or affinity reagents have been limited by the use of traditional, low-throughput technologies. In this thesis, we leverage recent advances in high-throughput DNA sequencing technology to develop new methods to characterize and probe the immune repertoire in unprecedented detail. We use this technology to 1) characterize the rapid dynamics of the immune repertoire in response to influenza vaccination, 2) characterize elite neutralizing antibodies to HIV, to better understand the constraints for designing an HIV vaccine, and 3) develop new methodologies for discovering auto-antigens, and assaying large libraries of protein antigens in general. We hope that these projects will serve as stepping-stones towards filling the gap left by low-throughput methods in the development of antibody technologies.
by Uri Laserson.
Ph.D.in Biomedical Engineering and Computational Biology
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Chang, Xing. "X-Linked FOXP3 & OTC in immune tolerance and autoimmunity." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1149171466.
Повний текст джерела
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Nelson, Debra Lynn. "The effect of perfluorodecanoic acid (PFDA) on parameters of the immune systems /." The Ohio State University, 1992. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487780393269062.
Повний текст джерела
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Vikberg, Martínez Yolanda. "REGIONAL SPECIALIZATION OF THEADAPTIVE IMMUNE SYSTEM WITHIN THEHUMAN GUT." Thesis, Örebro universitet, Institutionen för medicinska vetenskaper, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-73528.
Повний текст джерелаАнотація:
Background The human intestine is the largest immune organ in the human body and is constantly exposedto a great number of antigens and bacteria. This requires a balance between tolerogenic andimmunogenic responses to avoid inflammation. The small and large intestine have differentanatomy, physiological functions and are affected differently by diseases. Many studies onintestinal immunity do not distinguish between the small and large intestine, and most studiesare performed on mice. To fully understand human intestinal immunity, there is a need for morestudies on humans that also treat the different intestinal regions as separate compartments. Aim To summarize possible differences in the adaptive immune system in the human intestine, withspecial focus on antigen presenting dendritic cells and T lymphocytes. Methods A systematic review was performed on previously published articles that examined humanintestinal immunity with focus on adaptive immunity. The articles were obtained from thedatabase PubMed using MeSH terms. The articles were selected based on certain inclusion andexclusion criteria and their quality was evaluated. Results The collected data from included articles clearly show a difference in small and large intestinaladaptive immunity regarding distribution and functions of dendritic cells and T lymphocytes. Conclusion More knowledge about the differences in the properties of the immune system in differentregions of the intestine would probably contribute to a greater understanding of theimmunological basis of diseases affecting the intestines and might be valuable for developingnew treatment possibilities.
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Chan, Ying Kai. "Interplay of Dengue Virus and the Human Immune Response." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467339.
Повний текст джерелаАнотація:
RIG-I is a key cytosolic sensor of many RNA viruses, including dengue virus (DV), the most significant arboviral pathogen. Upon viral RNA binding, RIG-I signals via the adaptor protein MAVS, located at mitochondria, to induce the expression of interferons (IFNs), proinflammatory cytokines and interferon-stimulated genes (ISGs), thereby establishing an antiviral state. Among the ISGs, the IFITM proteins are critical for antiviral restriction of numerous pathogenic viruses including DV by inhibiting viral entry.
Here, we uncover how DV escapes RIG-I-mediated immunity. The NS3 protein of DV binds directly to 14-3-3ε, a mitochondrial-targeting protein that is essential for translocation of RIG-I from the cytosol to mitochondria. Specifically, NS3 blocks 14-3-3ε from forming a “translocon” complex with RIG-I and its upstream activator, TRIM25, thereby inhibiting RIG-I translocation to mitochondria for MAVS interaction and antiviral signaling. Furthermore, RIG-I that fails to translocate to mitochondria is degraded in a lysosome-dependent manner in DV- infected cells. Intriguingly, NS3 binds to 14-3-3ε using a phosphomimetic motif that resembles a canonical phospho-serine/threonine motif found in cellular 14-3-3-interaction partners. We engineer a recombinant DV encoding a mutant NS3 protein deficient in 14-3-3ε binding (DV2KIKP) and find that this mutant virus is attenuated in replication compared to the parental virus. Strikingly, DV2KIKP fails to antagonize RIG-I and elicits high levels of IFNs, proinflammatory cytokines and ISGs in human hepatocytes and monocytes. Taken together, our data reveal a novel phosphomimetic-based mechanism for viral antagonism of innate immunity and provide a foundation for DV vaccine development.
DV can infect cells directly, or complex with non-neutralizing antibodies to infect Fc- receptor-bearing cells in a secondary infection, which is associated with severe disease. While it has been shown that IFITMs restrict DV direct infection, it is unknown if the latter process, commonly termed antibody-dependent enhancement (ADE), might bypass IFITM-mediated restriction. Comparison of direct and ADE-mediated DV infection shows that IFITM proteins restrict both infection modes equally, suggesting that upregulation of IFITMs may be a therapeutic strategy.
In summary, our work elucidates several molecular aspects of the interplay of DV with the human immune response, which may guide the rational design of vaccines and antivirals.Medical Sciences
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Gascon, Merlos Mireia 1984. "Persistent organic pollutants, bisphenol A, phthalates and respiratory and immune health in childhood." Doctoral thesis, Universitat Pompeu Fabra, 2014. http://hdl.handle.net/10803/145922.
Повний текст джерелаАнотація:
Persistent organic pollutants (POPs), bisphenol A (BPA) and pthalates may increase the risk of respiratory infections and allergic diseases in infants and the effects might last until, at least, adolescence. Cytokines and biomarkers of inflammation can provide information of the mechanisms behind such associations. Data from the “Infancia y Medioambiente” (INMA) population-based birth cohort project and from six other existing European birth cohort studies have been used in the present thesis, which also includes a systematic review. Results of the present work, which includes five scientific publications, suggest that prenatal exposure to POPs affects the immune and respiratory health of children, that the effects are observed even at low levels of exposure and that these may last until adolescence. Biological mechanisms behind such effects were not possible to describe in the present thesis, however, it provided information of a potential biomarker (interleukin 10) of chronic immunotoxic effects of POPs. Results also indicate potential effects of prenatal exposure to BPA and phthalates on the development and functioning of the immune and respiratory systems of infants and children. In the present thesis we highlight the limitations of existing studies in the field and provide recommendations for future research.Els compostos orgànics persistents (COPs), el bisfenol A (BPA) i els ftalats podrien estar relacionats amb un increment del risc de patir infeccions respiratòries i símptomes relacionats amb l’al•lèrgia en infants i fins, com a mínim, l’adolescència. Les citoquines i els marcadors d’inflamació poden aportar informació dels mecanismes que hi ha darrera d’aquestes associacions. En la present tesis s’han utilitzat dades de la cohort de naixement “Infancia y Medioambiente” (INMA) i de sis cohorts de naixement Europees. La tesis també inclou una revisió sistemàtica. Els resultats d’aquest treball, que inclou cinc publicacions científiques, suggereixen que l’exposició prenatal a COPs afecta els sistemes immunitari i respiratori dels infants i nens, que aquests efectes es donen inclús a exposicions relativament baixes i que aquests efectes poden perdurar fins a l’adolescència. Els mecanismes biològics que podrien explicar els efectes observats no s’han pogut descriure en el present treball, tot i així, hem aportat informació d’un possible biomarcador (interleuquina 10) dels efectes immunotòxics crònics dels COPs. Els resultats també mostren efectes potencials de l’exposició prenatal a BPA i ftalats sobre el desenvolupament i funcionament dels sistemes immunitari i respiratori dels infants i nens. A la present tesis es remarquen les principals limitacions dels estudis existents en aquest camp i es proposen recomanacions de millora per a futurs estudis. Mentrestant, es recomana revisar la legislació actual per tal de reduir l'ús d'aquells compostos que encara estan al mercat i que s'utilitzen àmpliament.
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Munblit, Daniel. "Determinants of colostrum and breast milk immune composition and consequences for infant health." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/42364.
Повний текст джерелаАнотація:
Background: Breast milk is the principal source of nutrition during a critical period of immune programming - maternal and environmental exposures may influence breast milk composition and infant health. Objectives: To examine whether environmental and/or maternal factors influence levels of immune active components in colostrum and breast milk and identify associations between these factors and health outcomes. To examine if colostrum/breast milk immune composition can be grouped into specific 'lactotypes'. Methods: A prospective cohort study of mother/infant pairs in London, Moscow and Verona. Colostrum samples (days 0-6) and Mature Breast Milk (4-6 weeks) were analysed in duplicate using electrochemiluminescence, and the relationship between levels of immune active factors and maternal/environmental/infant factors was evaluated using mixed models. Lactotypes were identified using Principal Components Analysis. Results: Levels of immune active cytokines and growth factors in colostrum declined rapidly over time (r=-0.39 to -0.16; p<0.01). The effect of time could not be corrected using total protein or sodium as correction factors, due to different kinetics for each mediator measured. There were significant differences in colostrum and breast milk composition between countries, which could not be explained by the environmental and maternal factors examined. Using PCA there were two clusters of mediators, suggesting that four human breast milk 'lactotypes' exist, based on immune composition. There was some evidence in support of a relationship between human milk mediator levels and/or lactotypes, and infant health outcomes. Conclusions: The data support an important role for breast milk cytokines, and especially growth factor, levels as determinants of infant health. Further work is needed to identify improved methods for analysing colostrum and mature milk composition, which account for time of collection and/or stage of lactation.
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Glasper, Erica Renee. "Psychobiological factors alter health outcome." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1148415999.
Повний текст джерела
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Spriggs, Tracey Lynn. "MODULATION OF THE HUMORAL IMMUNE RESPONSE BY THE SYMPATHETIC NERVOUS SYSTEM." VCU Scholars Compass, 1994. https://scholarscompass.vcu.edu/etd/5519.
Повний текст джерелаАнотація:
The immune system is critical for the maintenance of homeostasis. Due to the fact that a coordinated effort between organ systems is required for internal stability, it has been postulated that the immune system interacts with the neuroendocrine system. Clinical, anatomical, and receptor studies have provided evidence for a bi-directional communication between the nervous and immune systems. The goal of the present studies was to determine the potential influence of the sympathetic nervous system (SNS) on the primary antibody forming cell (AFC) response.
The adrenergic neurotoxin, 6-hydroxydopamine (6-OHDA), has been utilized extensively by researchers to explore the possible relationship between SNS and the antibody response. However, the literature describing the humoral effects observed following 6-OHDA treatment is irresolute. In an attempt to provide insight into these apparent discrepancies, studies were conducted comparing the effects of 6-OHDA and its non-neurotoxic congener, 5-hydroxydopamine (5-OHDA). Both chemicals, when added directly into cultures containing naive splenocytes, suppressed the in vitro AFC response. Analysis following in vivo treatment with 6-OHDA or 5-OHDA revealed that while both chemical treatments resulted in suppression of the AFC response following in viva sensitization, only the splenocytes from 6-OHDA treated mice were suppressed when subsequently sensitized in vitro. Pretreatment with desmethylimipramine (DMI) blocked the observed 6-OHDA- and 5-OHDA-induced immunosuppression displayed in vivo, indicating that the uptake of the chemicals into adrenergic neurons was required. As an alternative method for removing the sympathetic influence in the spleen, studies were conducted with chlorisondamine, a non-competitive ganglionic blocker. While direct addition of chlorisondamine was without effect in the in vitro-in vitro AFC response, the in viva AFC response following chlorisondamine treatment was significantly suppressed.
In addition to the suppression of the primary AFC response, 6-OHDA and chlorisondamine treatment resulted in a time dependent increase in the level of DNA fragmentation in the thymus. Analysis of serum corticosterone levels in 6-OHDA- and chlorisondamine-treated mice revealed that both treatments elevated levels of serum corticosterone. Given the potential role of corticosterone in the 6-OHDA- and chlorisondamine-induced immunosuppression, studies were conducted to determine if the glucocorticoid receptor antagonist, RU-486, was able to block the DNA fragmentation in the thymus and the suppression of the AFC response demonstrated after 6-OHDA or chlorisondamine treatment. While RU-486 was effective at blocking the 6-OHDA- and chlorisondamine-induced thymic effects, it was unable to block the suppression of the primary AFC response. Collectively, these studies reveal that removal of the peripheral SNS by either sympathectomy with 6-OHDA or ganglionic blockade with chlorisondamine can result in 1) thymic alterations which are mediated by increased levels of corticosterone and 2) suppression of the primary AFC response which is independent of the elevated corticosterone levels. Importantly, these results provide evidence for positive modulation of the humoral immune response by the sympathetic nervous system.
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Chakir, Habiba. "Role of interleukin-12 and interleukin-18 in murine immune cell regulation." Thesis, University of Ottawa (Canada), 2003. http://hdl.handle.net/10393/28980.
Повний текст джерелаАнотація:
Interleukin 12 plays a central role in NK cell activation and CD4 +T cell differentiation. IL-12 acts via a receptor composed of IL-12Rbeta1 and IL-12Rbeta2 subunits. IL-12Rbeta1 plays a primary role in ligand binding whereas IL-12Rbeta2 is responsible for signaling. IL-18 shares some functional activities of IL-12. However, there is a considerable amount of contradictory data in the literature regarding the requirements for IL-12 and IL-18 responsiveness.
This work examined the expression of IL-12Rbeta2 on murine NK and T cells and the requirements for acquisition of IL-12/IL-18 responsiveness. NK cells stimulated with IL-2+IL-12 or IL-2+IL-18 exhibited rapid upregulation of IFN-gamma expression followed by upregulation of IL-10 or IL-13 mRNA, respectively. NK cells from IL-12Rbeta2-deficient mice responded to IL-2+IL-18 independently of IL-12. Furthermore, flow cytometric analyses revealed that NK cells activated in vitro with IL-2 differentiate into two distinct cell subsets expressing different levels of IL-12Rbeta2.
Like NK cells, NK-T cells also responded to IL-2+IL-12 or IL-2+IL-18 without stimulation of the antigen-specific T cell receptor (TCR). Previously, it was thought that all T cells require activation via the TCR in order to respond to IL-12 or IL-18. Thus, responsiveness of conventional T cells to IL-2+IL-12 or IL-2+IL-18 in the absence of TCR ligation was assessed. Naive CD4+T cells from wild type or DO11.10/Rag2-/- OVA-specific TCR transgenic mice responded to IL-2+IL-12 or IL-2+IL-18 by expressing IFN-gamma and cells grown in IL-2+IL-12 exhibited signs of polarization towards a TH1 phenotype.
Transgenic BALB/c mice constitutively expressing the IL-12Rbeta2 chain were generated and the role of the IL-12Rbeta2 in TH2 phenotype development was analyzed using the TH1-dependent murine leishmaniasis model. Despite constitutive expression of the IL-12Rbeta2 chain, transgenic TH2 cells did not revert to TH1 when restimulated with IL-12 and mice remained susceptible to Leishmania. The role of IL-12Rbeta2 in TH1 cell development was also analyzed using the same model. Resistant C57BL/6 mice defective in IL-12Rbeta2 gene exhibited susceptibility to L. major infection and expressed a T H2 phenotype, consistent with a critical role for IL-12 in this model.
Thus understanding the expression of IL-12Rbeta2 in NK and CD4 +T cells and its regulation by cytokines may constitute an important element in studies in cancer and autoimmune disease therapy.
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Faingold, Dana. "Immune expression and inhibition of heat shock protein 90 in uveal melanoma." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=92320.
Повний текст джерелаАнотація:
Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite the increase in diagnostic accuracy over the past several decades and the development of eye saving treatments such as plaque radiotherapy and photon beam therapy, there was no significant change in the prognosis in uveal melanoma due to metastatic disease. Therefore, we started to search for novel therapeutic targets in UM, such as heat shock protein 90 (Hsp90). This protein is a chaperone for several proteins (clients) involved in signal transduction and cell cycle control like kinases and transcription factors and plays a key role in regulating their stability and function. Hsp90 is expressed by a variety of tumor types and its inhibition results in the down regulation and proteasomal degradation of its client proteins.The objective of this study was to examine the immunohistochemical profile of Hsp90 and its association with prognostic features in uveal melanoma. In addition, we studied the role of Hsp90 in promoting growth and survival of uveal melanoma and the molecular consequences of inhibiting Hsp90 function by the small-molecule 17-allylamino-17-demethoxy-geldanamycin (17-AAG).
Hsp90 expression was studied in five primary human uveal melanoma cell lines by Western blot analysis and immunofluorescence methods in 44 specimens of human UM, 14 specimens from an animal model of UM and also in metastatic specimens.
In addition we determined the cytotoxicity profile of five primary UM cell lines and one metastatic derived cell line (OMM-1.5) after exposure to Hsp90 inhibitor 17-AAG. Sulfurhodamine-B based proliferation assay was used to compare UM cell growth with a range of concentrations of 17-AAG. Changes in cell migration and invasion and apoptosis and cell cycle assays were evaluated by flow cytometry. The expression of intracellular proteins was determined using Western blot analysis.
Hsp90 was identified in 68 % of cases of primary uveal melanoma and was expressed in 87% of metastatic specimens. The expression of the Hsp90 in primary tumor was significantly associated with largest tumor dimension.
Inhibition of Hsp90 function by 17-AAG caused a dose-dependent growth inhibition of primary and metastatic UM cell lines. 17-AAG induced cytostasis which was associated with a decrease in cyclin-dependent kinase CDK4. Also, 17-AAG induced apoptosis with a significant increase in caspase 3-protease activity after drug exposure. The cytotoxic effect of 17-AAG was associated with decreased levels of Akt and phospho-Akt after 24 h exposure to the drug. 17-AAG significantly reduced the migratory and invasive capabilities of all 5 uveal melanoma cell lines. 17-AAG down regulated c-Met and IGF-1R receptor transmembrane tyrosine kinases and also inhibited activation of focal adhesion kinase (FAK).
For the first time in UM, we demonstrate that over expression of Hsp90 in patients is linked to an indicator of poor prognosis. To the best of our knowledge, this is the first report showing the effect of Hsp90 inhibitor 17-AAG, on proliferation of UM cells which induced cell cycle arrest and apoptosis. Downregulation of p-Akt in response to Hsp90 inhibition could represent one possible mechanism of mod-ulation of the phosphatidylinositol 3'-kinase (PI3K)-Akt pathway in uveal melanoma. Also, we demonstrated for the first time that inhibition of Hsp90 function had an effect on UM cells motility and invasive potential and in cellular processes involved in metastasis in uveal melanoma. This data indicates that UM is a suitable target for modulation of Hsp90 activity and that Hsp90 inhibitors are possible therapeutic modalities for UM patients. Prospective studies are needed to confirm the prognostic role of Hsp90 in UM and further trials in uveal melanoma models should be undertaken to study the effect of inhibition of Hsp90 in vivo.
Le mélanome uvéal (UM) est la tumeur intraoculaire primitive la plus fréquente chez les adultes. Par conséquent, nous avons commencé à la recherche de nouvelles cibles thérapeutiques dans l'UM, tels que les protéines de choc thermique 90 (Hsp90). Hsp90 est une protéine chaperon indispensable à l'activation et la régulation d'un ensemble important de protéines de la signalisation et de la régulation cellulaire. L'utilisation d'inhibiteur spécifique de Hsp90 entraîne une baisse de l'activité des protéines clientes.
L'objectif de cette étude était d'examiner le profil des Hsp90 et son association avec les caractéristiques pronostiques dans mélanome de l'uvée. En outre, nous avons étudié le rôle qu'elle joue dans les mécanismes cellulaires de prolifération de mélanome de l'uvée et les conséquences de l'inhibition de la fonction de Hsp90 par 17-allylamino-17-demethoxy-geldanamycin (17-AAG).
L'expression immunohistochimique des Hsp90 a été étudiée dans cinq lignées de cellules tumorales in-vitro par Western blot et méthodes d'immunofluorescence. L'expression de Hsp90 a été évaluée dans 44 spécimens l'UM humaine et 14 spécimens d'un modèle animal de l'UM et dans des spécimens provenant de lésions métastatiques humaines et animales. En outre, notre étude a visé à comparer les effets antiprolifératifs du 17-AAG sur les lignées cellulaire cancéreuse d'UM humaine et dans une lignée de cellules tumorales dérivées d'une lésion métastatique (OMM-1,5). La prolifération cellulaire a été évaluée par le test à la sulforhodamine B sur les cellules exposées à une gamme de concentrations de 17-AAG.
Les changements dans la migration et l'invasion cellulaire en présence ou l'absence de la 17-AAG. Le processus apoptotique et les fractions de cycle cellulaire ont été déterminés par cytométrie en flux. Analyse de l'expression de Hsp90 et l'expression de protéines intracellulaires a été déterminée par l'analyse Western blot.
L'expression des Hsp90 a été identifiée dans 68% des spécimens et a été exprimée dans 87 % des spécimens métastatique. L'expression de l'Hsp90 dans la tumeur primaire a été significativement associée à la plus grande dimension de la tumeur.
L'inhibition de la fonction Hsp90 par 17-AAG a entraîné une inhibition de croissance dose-dépendante avec une réduction statistiquement significative. 17-AAG induit arrêt du cycle cellulaire qui a été associée à une diminution de la kinase CDK4. En outre, 17-AAG induisent l'apoptose dans les cellules d'UM et une augmentation de l'activité de la caspase-3. L'effet cytotoxique de la 17-AAG a été associé à une baisse des niveaux d'Akt et phospho-Akt, 24 h après l'exposition à la drogue.
L'exposition à la 17-AAG a considérablement réduit les capacités migratoires et invasives des les cinq lignées de cellules d'UM et provoquent une baisse des niveaux de récepteurs tyrosine kinases transmembranaires c-Met et IGF-1R et aussi a également réduit l'expression de la kinase d'adhérence focale (FAK).
Pour la première fois en UM nous démontrer que l'expression de Hsp90 chez des patients est liée à un indicateur de pronostic défavorable. Nos résultats apportent des informations originales sur les effets cytotoxiques de 17-AAG sur la prolifération des cellules d'UM qui induit un arrêt du cycle cellulaire et l'apoptose. Le diminution de p-Akt en réponse à Hsp90 inhibition pourrait constituer un mécanisme possible de la modulation de la phosphatidylinositol 3'-kinase (PI3K) - Akt signalisation de mélanome de l'uvée.
L'expression de Hsp90 dans métastases et l'évaluation des processus cellulaires impliqués dans l'invasion après l'inhibition de la fonction de Hsp90 suggéré l'utilité des inhibiteurs de Hsp90 dans la prévention de la progression tumorale et les métastases. L'ensemble de nos résultats montre que le ciblage Hsp90 mai constituer une nouvelle approche thérapeutique pour les patients avec le mélanome de l'uvée.
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Bennett, Patricia Helen. "Relationality and health : developing a transversal neurotheological account of the pathways linking social connection, immune function, and health outcomes." Thesis, Oxford Brookes University, 2013. https://radar.brookes.ac.uk/radar/items/bc0bd545-799e-455f-b5bc-40d74dcd946a/1/.
Повний текст джерелаАнотація:
This thesis is a transdisciplinary investigation of the link between social connection and health outcomes. Its twofold aim is to explore the nature of this relationship and build a theoretical model for a possible causal chain between the two, and to develop and deploy a new model for engaging the very different discourses of theology and neuroscience. To this end it draws on both theological reflection and on experimental scientific data from cognitive neuroscience and psychoneuroimmunology. The opening half of the work establishes the wider epistemological and methodological frameworks within which the project is set, and also the specific framework for the particular area of study. The first of these involves a critical analysis of the tensions at the heart of the dialogue between science and religion, and of the specific difficulties faced by the emerging sub-discipline of neurotheology. It then dissects and further develops the interdisciplinary dialogical model devised by J Wentzel van Huyssteen, in order to enable it to generate and support additional transdisciplinary outputs. In the second of the two framework arenas, the concept of health itself is first explored, and then epidemiological, Biblical, and immunological accounts of the link between relational connection and health are examined in order to establish that sufficient common ground exists to warrant a neurotheological approach to investigating the question of how the two are connected. The second half of the thesis then uses the developed model as a basis for engaging theological and neuroscientific perspectives on human relationality. This takes the form of three transversal encounters, each centred around a specific aspect of this: relationality as basic, as emergent, and as realised. From the output of these three dialogical interactions, a neurotheologically framed argument is developed to support the contention that relationality is an emergent phenomenon of a complex system concerned with social monitoring and response, and thus the way in which it is realised can exert causal constraints on system components. Finally a theoretical model is derived from this argument for a pathway linking relational experience to health outcomes via alterations in allostatic maintenance mechanisms.
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Minhas, Raman. "Cytokine-dependent hemopoietic cell linker : role in immune-cell receptor signaling." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=79052.
Повний текст джерелаАнотація:
Adaptor proteins provide mechanisms by which extracellular signals are amplified and downstream effector proteins are regulated. Cytokine-dependent hemopoietic cell linker (Clnk), a third member of the SLP-76 family of adaptor molecules, was previously shown to be a positive regulator of TCR signaling. To better understand the role of Clnk in the immune cell signaling network, we first sought to identify additional, unknown, Clnk-binding partners, ultimately confirming the known partners, namely HPK1 and Fyb. Further studies surrounding the Clnk-HPK1 interaction illustrated important binding regions between the two proteins. Stable transfection studies of Clnk in the SLP-76 deficient cell line, J14, revealed the ability of Clnk to rescue SLP-76 function, particularly in reference to optimal tyrosine phosphorylation and activation of Phospholipase C-gammal and MAP kinase. Transient transfections of the parental Jurkat T-cell line illustrated TCR-inducible, Clnk-dependent, gene promoter activation, including identification of novel downstream transcriptional targets such as the pro-apoptotic Nur77.
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Alter, Galit. "Fate of the HIV-specific immune response starting in primary infection." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84461.
Повний текст джерелаАнотація:
Two decades into the epidemic caused by the human immunodeficiency virus (HIV) and this virus has infected nearly 1% of the world's population. Highly active antiretroviral therapy (HAART) has transformed the epidemic from a death sentence into a chronic infection. However restricted access, complicated regimens, drug resistance, and long-term toxicities are all impediments to life long therapy for all those infected. These factors stress the need for vaccines and immunotherapeutic strategies that may be used in conjunction with antiretroviral drugs for the optimization of patient care.It is clear that cytotoxic T lymphocytes are potent suppressors of viral replication throughout the clinical course of HIV infection. The research presented in this thesis focuses on the characterization of immune responses at different stages of HIV infection in order to gain a better understanding of the pattern of changes that occur within the host response to virus on and off therapy following infection.
The HIV specific immune response broadens during the first two months of infection, suggesting that while it is induced early during acute infection, the antiviral response evolves to respond to the virus. HIV specific immune responses can be preserved if HAART is initiated while the subject is in early PI, and appears to depend on the preservation of HIV specific CD4+ T cell help. Subjects remaining untreated in PI experience significant perturbations (expansions and contractions) in responses to individual HIV peptides over a 1 year period, which is characterized by an overall contraction in the breadth and persistence in the magnitude of their antiviral effector activity.
New strategies that map the specificity, breadth and magnitude of the HIV specific immune response testing all HIV expressed gene products were evaluated. The novel approach will strengthen conclusions derived from the types of studies conducted for this thesis by detecting all reactivities present in subjects being tested in an unbiased manner. Interferon-gamma (IFN-gamma) secretion in response to epitopes previously unknown to be immunogenic are frequently detected using this screening method in subjects in the chronic phase of infection. Use of this technique demonstrates that HAART-naive HIV+ chronically infected subjects in asymptomatic disease target Gag predominantly and possess variable breadths and magnitudes of responses to HIV.
Taken together, the data presented in this thesis have improved our understanding of the pattern of the evolution of the immune response over time. Data presented here have implications for HIV infected patient management, by providing new information useful for deciding whether the immunological benefit of initiating HAART early in infection outweighs toxicities associated with long term treatment. Finally, new strategies for the detection of HIV specific immune responses will further our ability to characterize the global HIV specific immune responses at all stages of HIV disease.
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Abd-Elfatah, Hassan Ahmed. "Aspects on maternal immune health during gestation and early postpartum periods in the cow." Doctoral thesis, Universitat de Lleida, 2013. http://hdl.handle.net/10803/104487.
Повний текст джерелаАнотація:
Aquesta tesi (mitjançant cinc estudis) va ser destinada a investigar factors que tenen un efecte potencial sobre la salut materna durant la gestació i el postpart temprà, tenint en compte la melatonina com una possible millora de la salut i el rendiment de les vaques. En el primer estudi, els factors que afecten els leucòcits perifèrics de la mare, com un indicador d'estat immune, entre els dies 90-210 de gestació van ser, la interacció entre l'edat de la vaca i Neospora caninum, l'estació, la gestació gemelar, la producció de llet i el temps de mostreig. Seguint el sistema immune matern més enllà en la seva fase més crítica, el segon i el tercer estudis resumeixen els diferents factors que afecten el sistema immunològic de la mare des del dia 220 de gestació fins a 30 dies postpart. El toro d'IA, les glicoproteïnes associades a la gestació (PAG), la interacció N. caninum-C. burnetii, l'estació, l'edat, la gestació gemelar i el temps de mostreig afectaven significativament els leucòcits materns. L'objectiu del quart estudi va ser avaluar la dosi adequada de la melatonina, per provar els seus possibles efectes en la millora de la salut de la mare durant el peripart i la dosi de 332 mg / kg era la més adequada. Finalment, els possibles efectes de la melatonina en millorar la salut materna durant el peripart van ser avaluats en el cinquè estudi. Les vaques tractades amb melatonina tenien menys probabilitat de ser repetidores i de perdre la gestació, i, per tant, tenien menys dies oberts.Esta tesis (mediante cinco estudios) fue destinada a investigar factores que tienen un efecto potencial sobre la salud materna durante la gestación y el posparto temprano, teniendo en cuenta la melatonina como una posible mejora de la salud y el rendimiento de las vacas. En el primer estudio, los factores que afectan a los leucocitos periféricos de la madre, como un indicador de estado inmune, entre los días 90-210 de gestaion fueron, la interacción entre la edad de la vaca y Neospora caninum, la estación, la gestación gemelar, la producción de leche y el tiempo de muestreo. Siguiendo el sistema inmune materno más allá en su fase más crítica, el segundo y el tercer estudios resumen los diferentes factores que afectan al sistema inmunológico de la madre desde el día 220 de gestación hasta 30 días posparto. El toro de IA, las glicoproteínas asociadas a la gestación (PAG), la interacción N. caninum-C. burnetii, la estación, la edad, la gestación gemelar y el tiempo de muestreo afectaban significativamente los leucocitos maternos. El objetivo del cuarto estudio fue evaluar la dosis adecuada de la melatonina, para probar sus posibles efectos en la mejora de la salud de la madre durante el periparto y la dosis de 332 mg/kg era la más adecuada. Por último, los posibles efectos de la melatonina en mejorar la salud materna durante el periparto fueron evaluados en el quinto estudio. Las vacas tratadas con melatonina tenian menos probabilidad de ser repetidoras y de perder la gestación, y, por lo tanto, tenian menos días abiertos.
This thesis (by means of five studies) aimed at investigating factors that have potential effect on the maternal health during gestation and the early postpartum, plus considering melatonin for improving cows’ health and performance. In the first study, factors affecting maternal peripheral leukocytes, as an indicator to immune status, between Days 90-210 of gestaion were, the interaction between cows’ age and Neospora caninum-seropositivity, season, twin-pregnancy, milk production and time. Following the maternal immune system further in its most critical phase, the second and third studies summarize different factors affecting maternal immune system from gestation Day 220 till 30 days postpartum. Artificial inseminating bull, plasma pregnancy associated glycoproteins (PAGs), N. caninum-C. burnetii interaction, season, age, twin-pregnancy and time were found to significantly affect maternal peripheral leukocytes during that stage. The aim of the forth study was to evaluate proper melatonin dose as subcutaneous implants, for testing its possible effects in enhancing maternal health during the peripartum. Melatonin dose of 332 μg/kg was the most adequate. Finally, possible melatonin effects on enhancing maternal health during the peripartum were evaluated in the fifth study. Melatonin treated cows were found to have less likelihood of repeat breeding syndrome and pregnancy loss, and, therefore, less days open.
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McMenamin, Paul G. "The biology of immune cells in the eye : implications for development, health and disease." Thesis, University of Glasgow, 2009. http://theses.gla.ac.uk/3187/.
Повний текст джерелаАнотація:
The work presented in this thesis is a collection of papers from research spanning over 25 years. The research commenced whilst the candidate was employed in the Tennent Institute of Ophthalmology and later the Department of Anatomy at the University of Glasgow and continued in the School of Anatomy & Human Biology, The University of Western Australia. The research focuses on the biology of immune cells, primarily dendritic cells (DC), macrophages and mast cells, in the context of various components of the eye, including the aqueous outflow pathways, iris, cornea, ciliary body, choroid and retina, and the supporting tissues (lids and conjunctiva). The studies are broad in the sense that they deal with the role of these cells in development (such as removing the vascular networks around the developing lens), their normal homeostasis and function (distribution, phenotype, turnover and functional activity) and their role in models of a number of eye diseases. The findings are important in understanding the pathogenesis of diseases including bacterial keratitis, anterior uveitis, autoimmune uveoretinitis (endogenous posterior uveitis), toxoplasmic retinochoroiditis, age-related macular degeneration and ocular allergic responses, namely any ocular disease with an immune-mediated pathology. Many of the findings in the enclosed papers were firsts in the field and have shaped our understanding of ocular inflammatory disease. In part the success of some these studies was due to the novel method of performing immunostaining on tissue wholemounts dissected from small rodent eyes. These preparations provided unique ‘plan’ views of the complex networks of DCs and macrophages in the iris and choroid which previously had not been appreciated. In addition, the wholemount approach used in the characterisation and study of immune cells in delicate eye tissues, were applied to related studies of the meninges and choroid plexus of the brain. These studies were amongst the first to fully characterise distinct DC and macrophage networks in the pia, arachnoid, dura and choroid plexus. The research presented in the more recent publications have utilised a range of transgenic, knock-out, congenic and chimeric mouse models to elucidate the function of immune cells in the eye.
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Simpson, Joanne Elizabeth. "Immune regulation induced by apoptotic cells in health and in systemic lupus erythematosus (SLE)." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/23515.
Повний текст джерелаАнотація:
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease where failure to remove apoptotic cells, due to a defect in phagocytic cells, or deficient opsonisation, leads to secondary necrosis and the release of DNA and chromatin. The nuclear constituents from apoptotic cells are targeted by autoantibodies, which form immune complexes. Immune complex-mediated TLR9 activation of plasmacytoid dendritic cells (pDCs) and subsequent secretion of interferon (IFN-α) is thought to drive inflammation in SLE. It is currently believed that pDCs do not normally respond to apoptotic cells, as self-DNA is hidden from TLR9. However, DNA and chromatin expressed on membrane bound apoptotic bodies is essential for inducing IL-10 secreting regulatory B cells through TLR9 stimulation. The overall objective of this thesis was to understand how apoptotic cells influence immune responses in health and in patients with SLE. Splenic mouse pDCs were activated with the synthetic TLR7 agonist R848 and TLR9 agonists CpGB and CpGA and were co-cultured with apoptotic cells, or with freeze-thawed necrotic cells. PDCs co-cultured with apoptotic cells down-regulated the expression of CD40 and CD86. When pDCs were activated by R848 or CpGB, IL-10, IFN-γ and IL-6 secretion was significantly induced in the presence of apoptotic cells. PDCs so cultured induced T cells to secrete immune-regulatory IL- 10. In contrast, co-culturing apoptotic cells with pDCs activated by CpGA, augmented IFN-α secretion. These cytokine responses by pDCs were only stimulated by DNA on whole apoptotic cells; not by free nucleic acids derived from necrotic cells. This data demonstrates that the inflammatory context in which pDCs sense whole apoptotic cells is crucial to determining the threshold of tolerance to apoptotic self. It questions the perception that pDCs see all apoptotic cells and their necrotic cellular debris as dangerous and suggests that there may be something intrinsically different about SLE apoptotic cells, which causes inflammation. SNPs near ATG5, a protein of the cell survival pathway autophagy, have been linked to SLE susceptibility, but the role of autophagy in SLE pathogenesis is unclear. We hypothesised that dysfunctional autophagy is linked to abnormal apoptosis of SLE lymphocytes. Western blotting revealed that ATG5-ATG12 protein complex expression was significantly reduced in SLE lymphocytes and they failed to convert LC3-I to LC3- II, the hallmark of a functioning autophagy pathway, which caused accelerated secondary necrosis. Apoptotic SLE lymphocytes had an impaired ability to stimulate IL-10 secreting regulatory B cells and they induced pro-inflammatory cytokine secretion by monocyte-derived macrophages. Phagocytosis of apoptotic SLE lymphocytes by healthy macrophages was also impaired; however this was independent of ATG5 protein expression. The novel findings of this thesis suggest SLE apoptotic lymphocytes are intrinsically pro-inflammatory, which may be caused by diminished autophagy leading to an inability of lymphocytes to correctly execute apoptosis. Furthermore, inefficient clearance of SLE apoptotic cells results from a defect in the apoptotic cell, rather than the phagocytic cell.
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Travers, Rebecca. "Metabolic and immune system cross-talk in human adipose tissue." Thesis, University of Bath, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.665387.
Повний текст джерелаАнотація:
The overall aim of the work presented in this thesis was to further characterise aspects of metabolic and immune system cross-talk in human subcutaneous adipose tissue, with a particular emphasis on the potential role of T-lymphocytes in adipose tissue dysfunction and insulin resistance. Chapter 3 characterised macrophage and T-lymphocyte populations residing in adipose tissue from lean through to class I obese men. This work demonstrated that T-lymphocytes display increased activation with increased adiposity and that potential compensatory mechanisms may be present to help counteract adipose tissue inflammation. In Chapter 4, the same participants were exposed to a meal-based stimulus in order to examine the postprandial metabolic and inflammatory responses in blood and adipose tissue. Despite increased glucose and insulin responses in blood with obesity, there were no differences in inflammatory cytokine gene expression responses in adipose tissue. This suggests that mechanisms may be present to limit or dampen inflammatory output from adipose tissue after feeding in individuals with modestly increased adiposity. Chapter 5 examined metabolic and immune system changes to 50 % calorie restriction for 3 days, resulting in reduced serum leptin which was temporally associated with a reduction in blood T-lymphocyte activation. In adipose tissue, however, leptin gene expression/secretion was not reduced and neither was resident T-lymphocyte activation, indicating that there may be local tissue-specific responses of immune cells to caloric restriction. Chapter 6 characterised differences between obese individuals with either normal or impaired glucose tolerance, and their respective responses to 10 days of diet and activity modification. Overall, this thesis highlights key differences in properties of T-lymphocyte populations with increasing levels of adiposity and insulin resistance together with responses in adipose tissue and the immune system in times of feeding, severe calorie restriction and glucose lowering diet and activity.