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Al-Dahwi, Zaineb. "Impairment of protective immunity to intestinal helminthiases." To access this resource online via ProQuest Dissertations and Theses @ UTEP, 2007. http://0-proquest.umi.com.lib.utep.edu/login?COPT=REJTPTU0YmImSU5UPTAmVkVSPTI=&clientId=2515.
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Ronan, Edward. "Understanding vaccine induced protective immunity to Mycobacterium tuberculosis." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:c0d7b20f-e144-42f8-aa52-301d0938b0b3.
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The current worldwide epidemic of Mycobacterium tuberculosis infection is a huge global health problem. Widespread BCG vaccination remains a useful tool in combating this epidemic; however, its variable efficacy requires urgent development of novel vaccines against Mycobacterium tuberculosis. Such a candidate vaccine is a serotype 5 adenovirus expressing antigen 85A from M. tuberculosis (Ad85A). In animal models Ad85A confers significant protection when administered intra-nasally. The work in this thesis demonstrates that intra-nasal immunisation with Ad85A results in inhibition of M. tuberculosis growth in the lung early after infection, in contrast to the late inhibition induced by parenterally administered vaccines. Early inhibition correlates with the presence in the lung of a highly activated population of antigen-specific CD8 T cells, maintained for at least 6 months post-immunisation by persistent antigen. For intra-nasal Ad85A to be effective, the vaccine must be delivered into the lower respiratory tract, as immunisation targeting only the nasal-associated lymphoid tissue (NALT) does not result in protection. Following a change of animal facility, the lung immune response to intra-dermal immunisation with Ad85A increased and this route of immunisation now induced protection, though growth of M. tuberculosis was inhibited only late after infection. However, this response and protection can be altered by exposure to environmental mycobacteria. Further experiments showed that simultaneous respiratory and parenteral immunisations (SIM) act additively, where local lung immunity inhibits the growth of M. tuberculosis early after infection and systemic immunity protects later. SIM regimes generate greatly improved protection over either immunisation alone and do not depend on priming and boosting.
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Yu-Lin, Teoh. "Programming CD8 T cell memory development and protective immunity." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491759.
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In order to elicit the ideal set of memory CD8 T cells, rational vaccine design and planning for vaccination regimes require additional knowledge on factors which affect CD8 memory development. Together with the initial conditions under which priming occurs, aspects upstream of the CD8 response such as antigen processing, trafficking and presentation have the ability to influence both the development of the response as well as the type of memory population generated. The exceptional influence of these factors on the resultant CD8 T cell response has led to the concept of CD8 T cell programming, highlighting the potential to manipulate CD8 T cell memory development by simply modifying priming strategies. The work presented in this thesis examines the development of CD8 responses under different conditions of priming and antigen presentation and attempts to provide evidence of a correlation between primary response traits and the outcome of an immune response in terms of protective immunity. As the investigation of early CD8 T cell activation events is naturally impeded by the limitation of precursor frequency, studies were conducted using the F5 TCR transgenic (influenza nucleoprotein; NP) murine model in conjunction with recombinant viral vectors engineered to express the influenza nucleoprotein (NP)antigen (Chapter 3: Groundwork). Differences between primary CD8 T cell responses elicited against vaccinia virus (VV) and modified vaccinia Ankara virus (MYA) were assessed and parameters' such as the rate of activation, degree of recruitment, expansion-contraction kinetics as well as the rate of memory marker acquisition compared (Chapter 4: Vector Comparison). Although MYA was demonstrated to be less immunogenic than VV, inducing. less robust primary responses, antigen-specific CD8 T cells activated by MYA appeared to develop better effector and memory qualities. The profiles of CD8 T cell development induced by the administration of a single viral vector (VV) via two different routes were also investigated (Chapter 5: Effect of Infection Route). Systemic VV infection via Lv. resulted in the generation of CD8 responses that focused more strongly against recombinant inserted antigen than the viral vector and provided greater protection against a secondary challenge with influenza virus. Taken together, results from these chapters indicated that a larger memory population does not necessarily imply better protective immunity. Enhanced primary response traits such as speed, magnitude and degree of activation or CD8 T cell recruitment into response during priming, generally assumed to be desirable in a vaccination setting, were also found to have little correlation with degree of protection. Instead, effector function and recall capacity proved to correlate best with challenge resistance and may be useful in assessing the potential of new vaccine candidates for clinical trials. Finally, the impact of antigen and APC trafficking on CD8 responses was investigated (Chapter 6: Role of CAMs on the development of CD8 T cell responses) and cell-adhesion molecules were shown to play an important role in the initiation ofCD8 responses.
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Hicks, Alice Sophie. "Defining biomarkers of protective immunity and disease for tuberculosis." Thesis, St George's, University of London, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589943.
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Tuberculosis (TB) is still a significant global public health problem. The only current vaccine, BCG, gives variable protection, especially in adults. Several new vaccines are currently in clinical trials but no correlates of protective immunity to TB have been defined. Therefore, vaccines have to go through extensive pre-clinical assessments and clinical trials. Once identified, correlates of protection could be used as early end-points during clinical trials, reducing costs and easing the assessment of a greater number of vaccine candidates. In addition, more reliable biomarkers of TB disease are required so that measuring the effects of therapeutic interventions during drug and vaccine trials is more accurate. A genome-wide microarray was utilised to identify potential correlates of protection induced post-BCG vaccination and post-M. tuberculosis challenge, and to identify biomarkers of disease in the non-human primate model of tuberculosis. Gene expression profiles generated from peripheral blood mononuclear cells isolated during past vaccine efficacy studies were analysed in two species of macaque where the outcome of infection was known. Differentially expressed genes were identified in a series of pair-wise comparisons. Post-vaccination, no genes could be identified which were indicative of a protective immune response in both species. Six weeks post-challenge, gene expression profiles generated from animals able to control TB infection revealed an up-regulation of genes related to the Th17 response whereas animals that were unable to control infection showed up-regulation of a number of iron regulatory genes. This was further investigated at post-mortem using RT-PCR to detect iron regulatory genes in conjunction with analysis of serum iron and transferrin levels. An up- regulation of genes for ferritin, transferrin receptor, SLCllAl and SLCllA2 coupled with lower serum iron levels compared with disease controllers suggests that in animals unable to control infection, iron is redirected intracellularly where it is utilised by the mycobacteria for growth. • 4 34
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Vento, Kevin Leon. "Assessment of protective immunity following mucosal vaccination with Pseudomonas aeruginosa." Thesis, St George's, University of London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408031.
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Kamuyu, Gathoni. "Identifying merozoite targets of protective immunity against Plasmodium falciparum malaria." Thesis, Open University, 2017. http://oro.open.ac.uk/51139/.
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The observation that individuals living in malaria endemic regions who are repeatedly infected with P. falciparum can acquire immunity, first to severe, then to uncomplicated clinical episodes of malaria, and finally to high parasite densities, provides hope that a vaccine is achievable. Immunoglobulins have been identified as a key component of naturally acquired immunity and identifying the targets and mechanisms by which this protection is achieved is a clear research priority. To date, only a small proportion of the parasite proteome has been evaluated in the context of naturally acquired immunity. This thesis was aimed at contributing to this knowledge gap by identifying novel potential antigen targets of protective antibodies and validating these in samples from Tanzanian adults. First, to identify merozoite antigens that were immunogenic, I resolved proteins extracted from P. falciparum merozoites by two-dimensional gel electrophoresis and tested these for reactivity with immunoglobulins from malaria immune adults. Immunoreactive proteins were then identified by mass-spectrometry. In complementary studies, purified P. falciparum merozoites were treated with proteolytic enzymes to release proteins localised on the surface of merozoites, which were subsequently identified by mass-spectrometry. Using stringent criteria, where I combined the data obtained from 2D-immunoblots and surface-trypsinization experiments with bioinformatics prediction (for the presence of a signal peptide and/or transmembrane domain), I narrowed down to 222 potential merozoite vaccine targets. These included known surface and/or immunogenic proteins such as the 6-cysteine proteins (Pf12, Pf38, Pf41), MSP-1, 3, 7, 9, 10, GLURP, AMA1, GAMA, MTRAP, LSA3 and RhopH3 as well as many unstudied proteins. From the set of unstudied proteins, I prioritised 27 antigens for immunoprofiling and identified 19 antigens that are targets of naturally acquired antibodies and potential novel vaccine candidates. Next, using a cohort of adults living in a village in Tanzania that experiences hyperendemic malaria transmission throughout the year, I examined antibody responses to the novel potential vaccine candidates to test whether they were correlated with protective immunity. I began by identifying a panel of antigens that were immunogenic and elicited a stable antibody response in adults. Subsequently, I identified six antigens that were individually associated with protection from clinical episodes of malaria. Individuals who became ill during the follow-up period had significantly lower levels of these antibodies compared to those who did not. These antigens were the pantothenate transporter (PfPAT), a putative amino acid transporter (PF3D7_0629500), PF3D7_0830500, PF3D7_1025300, PF3D7_1345100 and PF3D7_1401600. In addition, the breadth of antibody responses to the tested antigens was associated with protection from clinical malaria. Finally, four of these six antigens strongly correlated with protective effector functions. Antibody responses to PfPAT were strongly correlated to both the ability to fix soluble factor C1q (C1q-fixation) to merozoites as well as with their interaction with neutrophils to release reactive species (ADRB). In addition, antibody responses to the putative amino acid transporter, PF3D7_1345100 and PF3D7_1401600 were strongly associated with C1q-fixation ability. Recruitment of the soluble factor C1q onto the surface of merozoite results in lysis via the classical complement pathway. The release of reactive oxygen species by neutrophils is thought to be toxic to the intra-erythrocytic stages of the parasites and is associated with parasite clearance. This thesis shows that 19 antigens, some of which have been studied for the first time in this work, are targets of naturally acquired antibody responses. Six of these antigens appeared to be associated with protective immunity to malaria in adults and correlated strongly with immune effector mechanisms that are thought to be important for parasite clearance. These findings provide a set of antigens that warrant further evaluation for inclusion into the vaccine pre-clinical development pipeline.
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Carrillo, Martha. "Studies on protective immunity to toxocara canis in laboratory animals /." The Ohio State University, 1989. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487671108307319.
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Scheckelhoff, Mark R. "Specific T cell repertoires mediate protective immunity to Histoplasma capsulatum." Cincinnati, Ohio : University of Cincinnati, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=ucin1051292258.
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Bereczky, Sándor. "Genetic diversity of Plasmodium falciparum infections : influence on protective malaria immunity /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-548-8/.
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Ali, Pirlanta Omer. "Schistosoma mansoni schistosomulum surface epitopes and their relevance to protective immunity." Thesis, Brunel University, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.253289.
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Israelsson, Elisabeth. "The role of antibody mediated parasite neutralization in protective immunity against malaria." Licentiate thesis, Stockholm University, Wenner-Gren Institute for Experimental Biology, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-7137.
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Lu, Hang. "Induction of protective immunity against chlamydial infection with antigen-pulsed dendritic cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0024/MQ51746.pdf.
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Infante, Duarte Carmen [Verfasser]. "Antigen-independent pathogenic and protective immunity in chronic neuroinflammation / Carmen Infante Duarte." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2013. http://d-nb.info/1043480854/34.
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Manning, Nicola. "Vaccination strategies for cross-protective immunity against African Horse Sickness Virus (AHSV)." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:43bb619c-81fb-4efe-81fc-e7423fa22b24.
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African Horse Sickness (AHS) is a highly lethal arboviral disease of equines. The lack of treatment makes vaccination essential. However, there are nine AHSV serotypes and AHSV immunity is serotype-specific; therefore AHSV vaccines must protect against all serotypes circulating in the field. A commercial polyvalent live-attenuated vaccine has been used for decades. However, bio-safety risks associated with its use, derived from gene segment re-assortment between vaccine and field strains, prompted the development of safer alternatives. These include the use of recombinant Modified Vaccinia Ankara virus (MVA). Previous studies showed that recombinant MVA vaccines expressing the AHSV outer-capsid VP2 protein successfully induced homologous protection and that a polyvalent MVA-VP2 vaccine could be developed (Manning et al., 2017). MVA vaccines expressing full length VP2 or fragments thereof, including a truncated-VP2 lacking the central VP2 immunodominant region, indicated that the structural integrity of VP2 was critical for preservation of neutralising epitopes. Further studies aimed at enhancing MVA-VP2 immunogenicity showed that monovalent MVA-VP2, expressing full-length VP2 from 'immediate-early' vaccinia promoters, could be used in a multivalent vaccination regime inducing homologous protection. To improve the design of polyvalent MVA-VP2 vaccines, a novel strategy based on using bivalent MVA-VP2, expressing two VP2 proteins from different serotypes, was proven successful. Homologous protection conferred by a bivalent MVA-VP2 for AHSV-4 and -9 was comparable to its monovalent counterpart. Previous studies showed MVA-VP2 immunogenicity depends on levels of VP2 protein presented to the immune system at the time of vaccination, since purified MVA-VP2 failed to induce virus neutralising antibodies (VNAb). Further studies described in this thesis, showed the addition of carbopol adjuvant improved immunogenicity of purified MVA-VP2 vaccines. MVA recombinants were produced expressing conserved AHSV capsid proteins, including VP5, VP7 and VP3, and immunogenicity of MVA-VP3 was tested which did not confer any protection against challenge. Various single and dual-expression MVA viruses were generated which will enable generating virus-like-particle AHSV vaccines by MVA expression, which has not been reported previously.
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SCHECKELHOFF, MARK ROBERT. "SPECIFIC T CELL REPERTOIRES MEDIATE PROTECTIVE IMMUNITY TO HISTOPLASMA CAPSULATUM." University of Cincinnati / OhioLINK, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1051292258.
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Mountford, A. P. "The induction of protective immunity in mice by attenuated larvae of Schistosma mansoni." Thesis, University of York, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381326.
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Bancroft, Allison J. "The BALB/c mouse as a model for protective immunity to Brugia pahangi." Thesis, University of Liverpool, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333631.
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Duprez, Jessica Anais Sybille. "Experimental vaccination for onchocerciasis and the identification of early markers of protective immunity." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/28976.
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Onchocerciasis, caused by Onchocerca volvulus remains a major public health and socio-economic problem across the tropics, despite years of mass drug administration (MDA) with Ivermectin to reduce disease burden. Through modelling, it has been shown that elimination cannot be achieved with MDA alone and additional tools are needed, such as vaccination, which remains the most cost-effective tool for long-term disease control. The feasibility behind vaccination against O. volvulus can be demonstrated in the Litomosoides sigmodontis mouse model, which shows that vaccine induced protection can be achieved with immunisation using irradiated L3, the infective stage of L. sigmodontis and with microfilariae (Mf), the transmission stage of the parasite. There is further evidence of protective immunity in humans, with individuals living in endemic areas that show no signs of infection despite being exposed to the parasite (endemic normal). The protective efficacy of promising vaccine candidates were evaluated using an immunisation time course in the L. sigmodontis model, using either DNA plasmid or peptide vaccines. In immunisation experiments in L. sigmodontis, Mf numbers are used as a measure of protection and marks the end of an immunisation time course. However, when changes in gene expression were measured at the end of an immunisation time course, in attempts to identify gene signatures that could be used as markers of protection (correlates of protection) in the blood, no gene signatures were found to be associated with protection. This suggest that at the end of an immunisation time course, when protection is measured (change in Mf numbers), it is too late in infection to measure changes in immune pathways being triggered. Changes in gene expression were therefore measured in blood samples collected throughout an immunisation time course in the L. sigmodontis model, in order to identify the time point in an immunisation experiment which are the most indicative of protection. Two independent immunisation time courses were used, either using irradiated L3 or Mf as vaccine against L. sigmodontis, as these elicit the greatest protection. This generated a large high dimensional dataset, that was too large and complex for a differential fold-change analysis. Therefore, an analysis pipeline was created using machine learning algorithms, to detect changes in gene expression throughout the time courses to detect markers of protection. The 6 hour time point following immunisation showed the greatest change in gene expression, with the analysis pipeline identifying known pathways associated with vaccine-induced immunity. The pipeline was applied to gene expression data from human samples obtained from individuals living in endemic areas who were either infected with O. volvulus or endemic normal (naturally protected), this was to identify pathways associated with protective immunity in humans. When comparing vaccine induced immunity seen in mice and natural protective immunity in humans there was some overlap in pathways being triggered, suggesting that similar pathways are needed for protection and that if a vaccine can trigger the right pathways in mice, it is likely to be effective in humans. Overall the machine learning analysis of the gene expression data, not only shows that it is feasible to measure change in gene expression in blood during filarial infections, but that during an immunisation time course it is the early time points following immunisation that are the most predictive of vaccine efficacy (protection outcome). One of the vaccine candidates, cysteine protease inhibitor-2 (CPI), is a known immuno-modulator that inhibits MHC-II antigen presentation on antigen presenting cells such as dendritic cells (DC). This candidate has consistently been shown to induce protection if its immuno-modulatory active site was modified. In in vitro studies, it was shown that modification of the active site of CPI rescues antigen presentation in DC. This shows the importance of DC activation before the onset of infection, demonstrating the importance of triggering protective responses early in infection, and provides insight on how one of the vaccine candidates achieves protection.
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Figueroa, Z. E. F. "Specificity and protective effect of polyclonal antibodies to antigens of Plasmodium berghei and Plamodium chabaudi." Thesis, Open University, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304217.
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Elliott, Lisa Medicine UNSW. "Correlates of protective immunity in individuals who are exposed to Hepatitis C but appear uninfected." Awarded by:University of New South Wales. Medicine, 2006. http://handle.unsw.edu.au/1959.4/27371.
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The hepatitis C virus (HCV) currently infects 3% of the world???s population, with chronic infection in 50-80% of exposed individuals. A small subset of individuals who are exposed to HCV do not develop anti-HCV antibodies, persistent viraemia or chronic hepatitis despite generating HCV-specific CD4+ and CD8+ T cells. These individuals are believed to develop an immune response which rapidly clears viraemia prior to the induction of an antibody response. Circumstantial evidence supports the likelihood that some of these individuals may generate these same responses and outcomes on repeated occasions of HCV infection. HCV-specific cellular immune responses in seronegative subjects have been the subject of only limited prior study, in part due to the lack of appropriate recombinant antigens and assay systems. Therefore, this thesis described the development and validation of an interferon-? (IFN-?) ELISPOT assay using overlapping peptides (n=441). Using this assay, HCV-specific cellular immune responses were detected in 5/10 (50%) of chronically infected subjects. Responses were identified more frequently, and were directed against more regions of the HCV genome, than with traditional assay systems. This IFN-? ELISPOT assay, a comparable interleukin (IL)-2 ELISPOT assay, and a multiplex in vitro cytokine production assay were then used to evaluate HCV-specific cellular immune responses in three cohorts of seronegative subjects at high-risk of exposure to HCV ??? babies born to infected mothers, multiply-transfused subjects with thalassaemia, and high risk injecting drug users. Cellular immune responses were evaluated in 23 infants born to HCV-antibody positive women. Responses were not detected in infants born to HCV-PCR negative mothers. IFN-? production was detected in 1/11 infants born to viraemic mothers using the ELISPOT assay, with cytokine production observed in an additional 3/5 infants studied using the in vitro cytokine production assay. HCV-specific cellular immune responses were assessed in a cohort of multiply transfused subjects with thalassaemia using assays for cytotoxic T lymphocyte activity, IFN-? and IL-2 ELISPOT, as well as lymphocyte proliferation and in vitro cytokine production. Responses were detected in 6/13 chronically infected subjects (46%), 4/7 subjects who had cleared infection (71%), and 14/17 seronegative subjects (82%). The seronegative subjects had responses which were broader and higher in magnitude than those with chronic HCV infection, although lower and narrower than in subjects who had cleared prior HCV infection. IFN-? and IL-2 ELISPOT assays, in additional to in vitro cytokine production assays, were performed on 41 injecting drug users (IDUs), with responses detected in 6 (15%). Seronegative IDUs with HCV-specific cellular immune responses had been injecting for a mean of 7.7 years, and reported multiple risk factors for exposure to HCV. The combined data from these three cohorts indicate that the HCV-specific cellular immune responses detected in seronegative subjects were generally broad in specificity. Cytokine production was generally Th1-biased, a pattern which has previously been associated with an increased likelihood of clearance in primary infection. The findings also suggest that responses can be maintained for decades after exposure, and may provide protection against repeated exposures. In summary, cellular immunity against HCV is evident in some seronegative high risk subjects, suggesting that the cellular immune responses may efficiently facilitate viral clearance. Understanding the mechanisms of this immune response pattern will allow better understanding of the host response to HCV and may provide key insights into vaccine design.
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Pasnik, David J. "Immunologic and Protective Effects of Vaccines for Mycobacterium marinum in Morone sp." Thesis, Virginia Tech, 2002. http://hdl.handle.net/10919/10157.
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Recombinant and DNA vaccines utilizing Mycobacterium sp. antigen 85A (Ag85A) were assessed for immunostimulatory and protective effects against M. marinum. Because of their known susceptibility to piscine mycobacteriosis, Morone sp. were utilized as the models for these studies.
The first study evaluated a recombinant vaccine with a Brucella abortus strain RB51 vector expressing the Mycobacterium bovis Ag85A. Striped bass (M. saxatilis) were inoculated at doses equivalent to 106, 107, 108, 109, and 1010 colony-forming units/fish. Vaccinated fish demonstrated significant specific humoral and cell-mediated immune responses towards the Ag85A in a dose-dependant manner. However, vaccinated fish failed to demonstrate cross-protective responses after live Mycobacterium marinum challenge 70 days post-vaccination.
A DNA vaccine was constructed utilizing the Mycobacterium marinum Ag85A gene and a commercially-available eukaryotic expression vector. Hybrid striped bass (M. saxatilis x M. chrysops) were immunized by intramuscular (i.m.) and intraperitoneal (i.p.) injection at doses of 5 μg, 25 μg, or 50 μg plasmid. These fish produced significant Ag85A-specific antibody and lymphoproliferative responses over those of control fish injected with saline or empty plasmid. Non-specific macrophage phagocytic and respiratory burst functions failed to exhibit significant upregulation after vaccination. Fish receiving the DNA vaccine developed protective responses to high-dose M. marinum challenge 90 days post-vaccination, as demonstrated by increased relative percent survival and by reduced splenic bacterial counts over control fish. Furthermore specific immunostimulatory and protective effects were significantly increased using higher vaccine doses and using the i.m. injection route.
Given these promising findings, the protective responses induced by the DNA vaccine were further investigated. Hybrid striped bass were injected with 25 μg or 50 μg plasmid i.m. and developed specific protective responses to high-dose M. marinum challenge 120 days post-vaccination. The 25 μg and 50 μg groups both developed more rapidly and significantly increased immune responses post-challenge over those of the control groups. The vaccination groups also demonstrated increased survival, reduced splenic bacterial counts, and reduced granuloma formation compared to the control groups. However, though the vaccination groups did not demonstrate the same acute effects post-challenge as the control groups, the vaccination groups ultimately developed increased splenic bacterial counts and granuloma formation, and eventually experienced 100% mortalities. Because piscine mycobacteriosis can affect virtually any species of fish, a vaccine against this disease could be widely beneficial to the aquaculture and ornamental fish industries. The vaccines in these studies exhibited significant immunostimulatory capabilities in Morone sp., but only the DNA vaccine showed promise for conferring protection against M. marinum challenge. Though the DNA vaccine only provided limited protection against high challenge doses, future studies may likely find enhanced protective effects against lower, more natural exposure doses.Master of Science
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Ing, Rebecca Yat Loo 1971. "Mechanisms of innate immunity to blood-stage malaria infection : role of dendritic cells in host-parasite interactions and induction of protective immunity." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=102510.
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A favorable outcome of blood-stage malaria infection requires immune responses that effectively eliminate the infection with minimum pathology to the host. There is strong evidence that the innate immune system is critical for initiating and shaping the subsequent adaptive immune response to blood-stage Plasmodium parasites. As sentinels of infection and potent activators of immunity, dendritic cells (DCs) are pivotally positioned to control the immune response to malaria and thereby influence the outcome of infection. Experiments performed in this thesis work aimed to determine the role of DCs in host-parasite interactions and subsequent induction of protective immunity to blood-stage malaria. Moreover, the studies described herein emphasize the critical contributions of key cytokines to DC responses and interactions with other cells of the innate and adaptive immune system during blood-stage malaria. Based on previous linkage analyses that identified interleukin (IL)-15 as a candidate in genetic regulation of host resistance to blood-stage malaria, we demonstrated that IL-15 is important for timely resolution of a primary infection with Plasmodium chabaudi AS and maximal production of Th1-type cytokines and antibodies. Notably, IL-15 was revealed to be a key early cytokine for optimal DC and natural killer (NK) cell function as well as IL-12-dependent IFN-gamma production following P. chabaudi infection. Next, we demonstrated the ability of DCs to recognize and phagocytose parasitized red blood cells (pRBCs) in a highly selective and actin-dependent manner. Following interaction with pRBCs in vitro or in vivo, DCs from malaria-resistant mouse strains were shown to express upregulated costimulatory molecules and secrete abundant Th1-polarizing cytokines, particularly IL-12 and IFN-gamma. These signals enable DCs to prime other immune cells such as NK cells and CD4+ T cells for maximal IFN-gamma production. Reciprocally, malaria-activated NK cells were shown to induce DC maturation and production of Th1-polarizing cytokines, thus propagating an innate feedback loop leading to induction of Th1 immunity. DCs from malaria-susceptible A/J mice, however, showed impaired Th1 priming in favor of selective induction of IL-10-secreting CD4+ T cells, suggesting DC-mediated activation of tolerance, not immunity, in hosts unable to control and survive blood-stage malaria. These findings provide novel and important insights into the DC-mediated immune mechanisms that initiate and regulate host resistance to blood-stage malaria infection.
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Francisco, Ngiambudulu Mbandu. "The role of cell type-specific tumour necrosis factor in protective immunity against neurotuberculosis." Doctoral thesis, University of Cape Town, 2013. http://hdl.handle.net/11427/8706.
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Includes bibliographical references.Neurotuberculosis is the most severe form of extra-pulmonary tuberculosis, characterised by the formation of rich foci a brain form of granulomas, and tuberculous meningitis. Granulomas contain mycobacteria by recruitment of immune cells that surround the bacteria. The cytokine tumour necrosis factor has been found to be involved in the recruitment of the immune cells and structure maintenance of granulomas. Tumour necrosis factor is a multifunctional proinflammatory cytokine which play a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) infection. This cytokine is synthesised by several cell types of hematopoetic origin, such as microglia/macrophages, neutrophils, dendritic cells and lymphocytes, and non-hematopoetic origin such as astrocytes and neurons. During neurotuberculosis, excess of tumour necrosis factor has been implicated in persisting hyperinflammation, however, deficiency of tumour necrosis factor lead to uncontrolled bacterial growth; both phenomena causing necrotic lysis. Thus, a need exists to investigate the contribution of tumour necrosis factor by specific cell types in the control of cerebral M. tuberculosis infection and its protective immune response. In this study, we investigated the role of tumour necrosis factor derived from neurons, microglia/macrophages, neutrophils, CD4+ and CD8+ T cells in host immunity against M. tuberculosis; using an experimental murine model with cell type-specific gene targeting. We found that mice deficient for tumour necrosis factor in neurons (NsTNF-/-), as well as from microglia/macrophages and neutrophils (M-TNF-/-) are not susceptible to M. tuberculosis infection with a phenotype similar to wild type mice. Interestingly, mice with ablation of tumour necrosis factor in myeloid (microglia/macrophages, neutrophils) and CD4+ and CD8+ T cells (MTTNF-/-) were highly susceptible to M. tuberculosis infection with a phenotype similar to that of complete deficient tumour necrosis factor (TNF-/-) mice, which succumbed by 21 days postinfection. Thus, it seems that the resistance observed in M-TNF-/- mice may be caused by the compensation of T cell-derived TNF whose function appeared as non-redundant. Impaired protective immunity observed in MT-TNF-/- and TNF-/- mice were related to alteration of cytokines and chemokines, and also to reduce antigen response and B cells IgM secretion. Our data suggest that neurons as well as microglia/macrophages and neutrophils derived tumor necrosis factor have a very limited role in protective cerebral immune responses. In MT-TNF-/- mice, TNF mediated protective immunity against cerebral M. tuberculosis infection requires primarily T cell-derived TNF as opposed to macrophage/neutrophil derived TNF. These findings may inform the development of immunomodulatory therapy strategies against neurotuberculosis.
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Darby, Matthew G. "Protective immunity against Nippostrongylus brasiliensis requires antigen presentation by IL-4Rα responsive B cells." Master's thesis, University of Cape Town, 2012. http://hdl.handle.net/11427/14954.
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Includes bibliographical references.Nippostrongylus brasiliensis is a parasitic nematode infection that affects rodents. B-cells have been shown to play an important role in immunity to many different infections by antibody production and T-cell activation. But B-cell function in the protective TH2 response against N. brasiliensis infection is an area of immunity that is currently not well defined. Recently, it has been shown that B-cells are essential to the resolution of a Heligomosomoides polygyrus infection, another parasitic helminth. Our aim in this study was to investigate any role that B-cells may play in response to a secondary N. brasiliensis infection by analysing the differences in immunity of wild-type and B-cell-specific IL-4Rα knockout mice after a N. brasiliensis re-infection.
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Braun, Jan Matthias. "The role of commensal bacteria in the development of protective immunity to meningococcal disease." Thesis, University of Edinburgh, 2001. http://hdl.handle.net/1842/22775.
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Neisseria meningitidis (NM) is a major pathogen associated with severe and often fatal meningitis and septicaemia world-wide. Effective vaccines based on the capsular antigens for serogroups A,C,W135 and Y are available. The capsule of serogroup B, responsible for much of the endemic disease in industrialised countries, is not immunogenic and other approaches to development of an effective vaccine are being examined. Carriage of the commensal species Neisseria lactamica (NL) and Moraxella catarrhalis (MC) coincides with progressive increase in the level of natural immunity against NM. The aims of this project were: 1) to identify strains of NL and MC expressing antigens cross-reactive with NM; 2) to assess the functions of the cross-reactive antibodies induced by the commensal, e.g., complement mediated lysis and phagocytosis or neutralisation of lipooligosaccharide (LOS) toxicity; 3) to identify the antigens inducing cross-reactive antibodies; 4) to develop a model system using human cells to assess toxicity of vaccine candidates and their ability to induce neutralising or opsonic antibodies. Commensal isolates from different regions of Europe were used to absorb pooled human serum from individuals with no history of meningococcal disease. The pool had antibodies bactericidal against meningococcal isolates expressing a variety of phenotypes. These included isolates from patients, carriers and reference strains expressing different lipooligosaccharide (LOS) determinants. Strain NL1 from Scotland absorbed bactericidal antibodies against the greatest number of NM isolates and a broad range of phenotypes. Strain NL6 from Greece absorbed antibodies against only a few NM strains and isolates from Iceland and the Czech Republic showed intermediate patterns of absorption. Strain MC1 absorbed bactericidal and opsonising activities against significantly more NM strains expressing different phenotypes than strain MC2.
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Constant, Stephanie Louise. "The induction of protective immunity to Schistosoma mansoni in mice : in vivo lymphocyte responses in the draining lymph nodes." Thesis, University of York, 1991. http://etheses.whiterose.ac.uk/10854/.
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Zhang, Wenbao. "Echinococcus granulosus : studies of protective immunity, and the isolation and characterisation of stage-specific genes /." [St. Lucia, Qld.], 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17257.pdf.
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Lechner, Christian [Verfasser], and Peter [Akademischer Betreuer] Soboslay. "Immune Regulation and Protective Immunity during Helminth and Protozoan Infections / Christian Lechner ; Betreuer: Peter Soboslay." Tübingen : Universitätsbibliothek Tübingen, 2014. http://d-nb.info/1162897252/34.
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Hirst, Ian David. "Characterisation of the iron uptake mechanisms of Aeromonas Salmonicida : role in virulence and protective immunity." Thesis, University of Stirling, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317419.
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Patel, Rajen. "Dendritic Cells Mediate Protective Immunity Against Salmonella Typhimurium by Regulating Antigen Presentation, Inflammation and Cell Death." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34307.
Full textAbstract:
Salmonella enterica serovar Typhimurium (ST) is an intracellular bacterium that resides within the phagosome of infected cells. ST is the causative agent of gastroenteritis in humans and typhoid like disease in mice. ST infects epithelial cells and phagocytic cells such as dendritic cells (DCs), which are immune sentinels that have been regarded as the most critical antigen-presenting cell (APC). I evaluated the role of CD8α DCs, a subset of DCs capable of antigen presentation of phagosomal pathogens to activate CD8+ T cells. Furthermore, I assessed the role of key cytokines such as the group of classical anti-viral cytokines known as Interferon-I (IFN-I), on licensing CD8+ T cells. Interestingly, IFN-I signalling was necessary for production of inflammatory cytokines and induction of cell death, which activated CD8+ T cells and clearance of ST. Lastly, I examined the role of key cell death pathways in innate immune protection against ST. In particular, I addressed how signalling pathways in necroptosis and pyroptosis are critical for the production of IL-1beta and IL-18 which mediate immune protection against ST. Determining the mechanisms of which DCs engage innate and adaptive immune responses against phagosomal bacteria is the central question of my study and is addressed by examining critical roles of DC function, inflammation and cell death.
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Kleynhans, Leanie. "The impact of the steroid hormones medroxyprogesterone acetate, cortisol and progesterone on protective immunity to tuberculosis." Thesis, Stellenbosch : Stellenbosch University, 2012. http://hdl.handle.net/10019.1/20371.
Full textAbstract:
Thesis (PhD)--Stellenbosch University, 2012.Bibliography
ENGLISH ABSTRACT: Most individuals latently infected with Mycobacterium tuberculosis (Mtb) contain the infection by a balance of effector and regulatory immune responses. However, this balance can be influenced by steroid hormones such as glucocorticoids (GCs), which are known to increase the risk of reactivation of TB. The contraceptive medroxyprogesterone acetate (MPA), which also possesses selective glucocorticoid activity, is widely used in developing countries with approximately 60% of women on contraceptives using MPA in our study cohort. Therefore, our aim was to investigate the effect of this hormone on protective immune responses to BCG in HIV negative household contacts of active TB patients. When PBMCs of TB household contacts were stimulated with BCG in the presence of 10 μM MPA; this hormone displayed both glucocorticoid as well as progestogenic properties. Similarly to cortisol, MPA suppressed antigen specific expression of a range of cytokines including IL-1α, IL-1ra, IL- 17, TNFα, IL-5 and IFNγ. Dose response curves showed that MPA can also alter expression of some cytokines at lower contraceptive doses (in the nano molar range). To assess whether this effect of MPA in vitro also occurs in women using this hormone as contraceptive the PBMCs of MPA users and controls were stimulated with BCG and the levels of up to 29 different cytokines measured by luminex analysis. PBMCs of MPA users produced significantly lower levels of cytokines involved in immune responses against Mtb such as IL-12p40, IL-1α, IL-10, IL-13 and G-CSF, which corresponds with lower numbers of circulating monocytes observed in these women. These findings warrant further investigation and clinical trials should investigate the risk of progression from latent to active TB disease in women using this contraceptive. These trials, however, require a large number of participants and are prohibitively expensive; therefore it was decided to setup an Mtb/MPA mouse model to determine the effect of MPA on the disease outcome. BALB/c and C57BL/6 mice were injected with a weekly dose of one mg MPA or PBS and infected with 30 colony forming units of Mtb H37Rv one week after commencing the hormonal treatment. Both strains were included to establish which strain best represents the human model. Three and eight weeks post infection the MPA treated C57BL/6 mice had a significantly higher bacterial load in their lungs compared to untreated mice, whereas no difference was found in the bacterial loads of the BALB/c mice. MPA treated C57BL/6 mice had significantly lower serum levels of IL-10 and G-CSF and MPA treated BALB/c mice lower serum levels of IFNγ, when compared to untreated mice. Furthermore, cells isolated from the MLNs of MPA treated C57BL/6 mice, produced significantly less TNFα, significantly more IP-10 and less IL-10 in response to PPD, while MLN cells of MPA treated BALB/c mice produced significantly less IFNγ, IL-2, IL-17, GM-CSF and MCP-1. Data of the C57BL/6 mouse strain correlated with our human data and can it therefore be said that the C57BL/6 mouse strain, together with the serum concentration of MPA used in these experiments, is a good model to determine the effect of MPA in the context of a low dose Mtb infection. To conclude MPA use could therefore alter susceptibility to TB, TB disease severity as well as change the efficacy of new BCG-based vaccines, especially prime-boost vaccine strategies which may be administered to adult of adolescent women in the future.
AFRIKAANSE OPSOMMING: Die meeste mense wat latent met Mycobacterium tuberculosis (Mtb) geïnfekteer is, hou die infeksie onder beheer deur ʼn balans te handhaaf tussen effektor en regulatoriese immuunresponse. Hierdie balans kan egter beïnvloed word deur steroïedhormone soos glukokortikoïede (GCs), wat bewys is om die risiko van die heraktivering van TB te verhoog. Die voorbehoedmiddel medroksiprogesteroon-asetaat (MPA), wat ook selektiewe glukokortikoïed-aktiwiteit toon, word wyd gebruik in ontwikkelende lande en omtrent 60% van die vrouens in ons studie-bevolking wat voorbehoedmiddels gebruik, gebruik MPA. Om dié rede wou ons die effek van hierdie hormoon op die beskermende immuun-response teenoor M.bovis Bacilli Calmette-Guérin (BCG) in HIV negatiewe huishoudelike kontakte (HHKe) van pasiënte met aktiewe TB ondersoek. Ons het gevind dat wanneer perifere bloed mononukleêre selle (PBMSe) met BCG gestimuleer word in die teenwoordigheid van 10 μM MPA, hierdie hormoon beide glukokortikoïede en progesterogeniese eienskappe toon. Soos kortisol het MPA die antigeenspesifieke-uitdrukking van ʼn reeks sitokiene, insluitend IL-1α, IL-1ra, IL-17, TNFα, IL-5 en IFNγ, onderdruk. Respons kurwes wat verskillende konsentrasies van hormoon insluit, het getoon dat MPA ook by laer (nano-molare) dosisse die uitdrukking van sommige sitokiene kon verander. Om te bepaal of hierdie in vitro effek van MPA ook in vrouens wat MPA as voorbehoedmiddel gebruik voorkom, het ons PBMSe van MPA-gebruikers and kontroles met BCG gestimuleer en die vlakke van tot 29 verskillende sitokiene met behulp van Luminexanalise gemeet. PBMSe van MPA-gebruikers produseer beduidende laer vlakke van IL-12p40, IL-1α, IL- 10, IL-13 en G-CSF, wat elk in imuunafweerreaksies teen Mtb betrokke is. Die afname in dié sitokiene het gepaard gegaan met laer hoeveelhede sirkulerende monosiete. Ons resultate regverdig verdere ondersoeke en kliniese proewe behoort die risiko van progressie vanaf latente tot aktiewe TB in vrouens wat hierdie voorbehoedmiddel gebruik te bepaal. Sulke proewe vereis egter groot getalle deelnemers en is skrikwekkend duur, om die rede het ons besluit om ʼn Mtb/MPA muis-model op te stel om sodoende die algehele effek van MPA op die uitkoms van die siekte te bepaal. BALB/c en C57BL/6 muise is met ʼn weeklikse dosis van een mg MPA of sout oplossing ingespuit en een week na die aanvang van die hormoon behandeling met 30 kolonie-vormende eenhede Mtb H37Rv geïnfekteer. Beide muis tipes was ingesluit om sodoende te bepaal watter tipe die mens data die beste verteenwoordig. Drie en agt weke na die infeksie het die MPA-behandelde C57BL/6 muise ‘n beduidende hoër bakteriële lading in hul longe gehad as die onbehandelde muise, maar was daar geen verskil in die bakteriële ladings in die longe van die BALB/c muise nie. MPA-behandelde C57BL/6 muise het beduidende laer serumvlakke van IL-10 en G-CSF gehad, terwyl MPA-behandelde BALB/c muise laer serumvlakke van IFNγ gehad het. Verder het ons gevind dat die geisoleerde limfosiete van MPA-behandelde C57BL/6 muise beduidend minder TNFα, beduidend meer IP-10 en minder IL-10 geproduseer het na stimulasie met PPD, terwyl die limfosiete van MPA-behandelde BALB/c muise beduidend minder IFNγ, IL-2, IL-17, GM-CSF en MCP-1 geproduseer het. Data van die C57BL/6 muise stem ooreen met die van ons mens studie en ons kan dus vermeld dat die C57BL/6 muise, tesame met die spesifieke serumkonsentrasie van MPA wat gebruik is, ʼn goeie model is om die effek van MPA in die konteks van ʼn lae-dosis Mtb-infeksie te bestudeer. MPA gebruik kan dus die vatbaarheid vir TB, asook die erns van die siekte verander en kan ook die effektiwiteit van nuwe BCG-gebaseerde entstowwe, veral prima-hupstoot enstowwe, wat moontlik in die nabye toekoms vir volwasse en adolessente vroue toegedien kan word, verander.
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Thompson, Bridget. "Murine acute myeloid leukemia cells expressing the cytosine deaminase gene induce protective immunity to parental leukemic cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0020/MQ54149.pdf.
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Rapp, Ulrike. "Achieving protective immunity against intracellular bacterial pathogens a study on the efficiency of Gp96 as a vaccine carrier /." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=971616167.
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Contreras, Rojas Andrea Paz. "Brucella abortus RB51 vaccine: Testing its Spectrum of Protective and Curative Characteristics." Diss., Virginia Tech, 2004. http://hdl.handle.net/10919/28887.
Full textAbstract:
Brucella abortus (BA) are gram-negative, facultative intracellular bacteria that cause abortions in cattle and debilitating illness in humans. The US is now virtually free of bovine brucellosis, but the disease is endemic in wildlife. The official brucellosis vaccine in the US is strain RB51 (RB51). It elicits protective cell-mediated immunity (CMI) against BA infections.
Mycobacterium avium subspecies paratuberculosis (MAP) causes paratuberculosis in ruminants. It is a slow growing intracellular parasite that requires CMI for its control, belongs to the genus Mycobacterium, and is closely related to M. avium avium (MA).
Using RB51 as a vector that induces strong protective CMI may be useful to protect against MAP if it expresses MAP protective antigens. Therefore, MAP 85A and 35kDa proteins were expressed at low levels in RB51, and the immune responses elicited by these vaccines in BALB/c mice were evaluated. Strong anti-Brucella immunity was generated, but the anti-mycobacterial response was low. To evaluate protective efficacy, a BALB/c model using MA was developed. When mice were challenged with MA, protection was obtained in some experiments but was inconsistent. This may be due to the low expression of MAP antigens in RB51.
Another objective was to evaluate the effect of an ongoing Brucella-infection on the efficacy of RB51 vaccination, and whether vaccination of already infected animals could have a curative effect. Mice acutely or chronically infected with virulent BA, rapidly cleared the RB51 vaccine organisms, but there was no significant decrease in the number of virulent BA.
Brucella spp. have been developed as biological weapons, but there are no vaccines to protect humans. The development of a very attenuated protective vaccine is necessary to prevent human infections, as well as to protect wildlife. To generate such a vaccine, RB51 based vaccines were irradiated to render them non-replicative, but metabolically active. We demonstrated that in general, irradiated and non-irradiated RB51 vaccines remain protective at levels similar to those elicited by the live vaccines. Therefore, irradiation of strain RB51 is an effective means of attenuating the strain without affecting its protective characteristics, and could eventually be used as a vaccine for wildlife and humans.Ph. D.
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Prince, Amanda L. "The Role of Inducible T Cell Kinase (Itk) in the Development of Innate T Cells and in the Formation of Protective Memory Responses: A Dissertation." eScholarship@UMMS, 2013. https://escholarship.umassmed.edu/gsbs_diss/660.
Full textAbstract:
T cell development in the thymus produces multiple lineages of cells, including conventional naïve CD4+ and CD8+ T cells, regulatory T cells, and innate T cells. Innate T cells encompass γδ T cells, invariant natural killer (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and H2-M3-restricted cells (Berg, 2007). Although they are a minor subset of all thymocytes, innate T cells develop in the thymus and share characteristics of the innate and adaptive immune systems (Berg, 2007). These lymphocytes undergo antigen receptor rearrangement and are able to exert their effector function immediately upon ex vivo stimulation (Berg, 2007). However, in several strains of mice harboring mutations in T cell signaling proteins or transcriptional regulators, conventional CD8+ T cells develop as innate cells that share characteristics with memory T cells (Atherly et al., 2006b; Broussard et al., 2006; Fukuyama et al., 2009; Gordon et al., 2011; Verykokakis et al., 2010b; Weinreich et al., 2010). One of these signaling proteins, inducible T cell kinase (Itk) is a nonreceptor protein tyrosine kinase that signals downstream of the T cell receptor (TCR) (Berg et al., 2005). Upon TCR activation, Itk is activated and recruited to the TCR signaling complex, where Itk interacts with Src homology 2 (SH2) domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76), linker for activation of T cells (LAT), and phospholipase C γ1 (PLCγ1) (Berg et al., 2005). Thus, in Itk-deficient mice, TCR signaling is disrupted, which results in mature CD4- CD8+ (CD8SP) thymocytes that are CD44high, CD62Lhigh, CD122+, and CXCR3+ and that express high levels of the transcription factor, Eomesodermin (Eomes) (Atherly et al., 2006b; Broussard et al., 2006; Weinreich et al., 2010). Recently, it was determined that the development of these innate CD8SP thymocytes in itk-/- mice is dependent on IL-4 produced in the thymic environment by a poorly characterized subset of CD3+ thymocytes expressing the transcriptional regulator, promyelocytic leukemia zinc finger (PLZF) (Gordon et al., 2011; Verykokakis et al., 2010b; Weinreich et al., 2010). Here we show that a sizeable proportion of mature CD4+ CD8- (CD4SP) thymocytes in itk-/- mice also develop as Eomesodermin+ innate T cells. These Eomes+ innate CD4+ T cells are CD44high, CD62Lhigh, CD122+, and CXCR3+ (Atherly et al., 2006b; Broussard et al., 2006; Dubois et al., 2006; Weinreich et al., 2010). Surprisingly, neither CD4SP nor CD8SP innate thymocytes in itk-/- mice are dependent on γδ T cells for their development as was previously hypothesized (Alonzo and Sant'Angelo, 2011). Instead, both subsets of innate itk-/- T cells require the presence of a novel PLZF-expressing, SAP-dependent thymocyte population that is essential for the conversion of conventional CD4+ and CD8+ T cells into Eomesodermin-expressing innate T cells with a memory phenotype. This novel subset of PLZF-expressing SAP-dependent innate T cells preferentially home to the spleen and mesenteric lymph nodes and have a restricted TCR repertoire. Thus, we have christened this subset as CD4+ PLZF + MAIT-like cells. We have characterized multiple subsets of innate T cells that expand in the absence of Itk. Therefore, we were interested in how innate T cells respond to infection. Although Itk KO mice have defects in cytolytic function and cytokine production during an acute infection, these mice are able to clear viral infections (Atherly et al., 2006a; Bachmann et al., 1997). Hence, we hypothesized that Itk-deficient memory CD8+ T cells would be able to provide protection upon a challenge infection. Conversely, we found this not to be true although Itk-deficient memory CD8+ T cells were present in similar frequencies and cell numbers as WT memory CD8+ T cells at 42 days post-infection. Furthermore, Itk-deficient memory CD8+ T cells were able to produce IFNγ and exert cytolytic function upon stimulation. Although the function of Itk-deficient memory CD8+ T cells appeared to be intact, we found that these cells were unable to expand in response to a challenge infection. Remarkably, conventional memory CD8+ T cells lacking Itk were able to expand and form protective memory responses upon challenge. Thus, the inability of Eomes+ innate CD8+ T cells to form protective memory responses does not appear to be intrinsic to cells deficient in Itk. This thesis is divided into six major chapters. The first chapter will provide an introduction to T cell development and the role of Itk in T cell development. Additionally, it will introduce a variety of innate T cell subsets that will be discussed throughout this thesis and will provide an overview of CD4+ and CD8 + T cell differentiation during infection. This section will explain the role of Itk in CD4+ helper T cell differentiation and describe how Itk-deficient CD8+ T cells respond to acute infection. The introduction will also discuss the generation of conventional memory CD8+ T cells. The second chapter will provide the details of the experimental procedures used in this thesis. The third chapter will describe the characterization and development of Eomes+ innate CD4+ T cells that develop in the absence of Itk. Additionally, this chapter will address the subset of PLZF+ innate T cells that induce the expression of Eomes in innate T cells. The fourth chapter will further characterize and explore the development of itk-/- CD4+ PLZF+ MAIT-like T cells. The fifth chapter will examine the role of Eomes + innate CD8+ T cells in protective memory responses. Chapters three through five will display work that is in preparation to be submitted to a peer-reviewed journal. The sixth chapter will discuss the results of this thesis and their implications.
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Prince, Amanda L. "The Role of Inducible T Cell Kinase (Itk) in the Development of Innate T Cells and in the Formation of Protective Memory Responses: A Dissertation." eScholarship@UMMS, 2002. http://escholarship.umassmed.edu/gsbs_diss/660.
Full textAbstract:
T cell development in the thymus produces multiple lineages of cells, including conventional naïve CD4+ and CD8+ T cells, regulatory T cells, and innate T cells. Innate T cells encompass γδ T cells, invariant natural killer (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and H2-M3-restricted cells (Berg, 2007). Although they are a minor subset of all thymocytes, innate T cells develop in the thymus and share characteristics of the innate and adaptive immune systems (Berg, 2007). These lymphocytes undergo antigen receptor rearrangement and are able to exert their effector function immediately upon ex vivo stimulation (Berg, 2007). However, in several strains of mice harboring mutations in T cell signaling proteins or transcriptional regulators, conventional CD8+ T cells develop as innate cells that share characteristics with memory T cells (Atherly et al., 2006b; Broussard et al., 2006; Fukuyama et al., 2009; Gordon et al., 2011; Verykokakis et al., 2010b; Weinreich et al., 2010). One of these signaling proteins, inducible T cell kinase (Itk) is a nonreceptor protein tyrosine kinase that signals downstream of the T cell receptor (TCR) (Berg et al., 2005). Upon TCR activation, Itk is activated and recruited to the TCR signaling complex, where Itk interacts with Src homology 2 (SH2) domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76), linker for activation of T cells (LAT), and phospholipase C γ1 (PLCγ1) (Berg et al., 2005). Thus, in Itk-deficient mice, TCR signaling is disrupted, which results in mature CD4- CD8+ (CD8SP) thymocytes that are CD44high, CD62Lhigh, CD122+, and CXCR3+ and that express high levels of the transcription factor, Eomesodermin (Eomes) (Atherly et al., 2006b; Broussard et al., 2006; Weinreich et al., 2010). Recently, it was determined that the development of these innate CD8SP thymocytes in itk-/- mice is dependent on IL-4 produced in the thymic environment by a poorly characterized subset of CD3+ thymocytes expressing the transcriptional regulator, promyelocytic leukemia zinc finger (PLZF) (Gordon et al., 2011; Verykokakis et al., 2010b; Weinreich et al., 2010). Here we show that a sizeable proportion of mature CD4+ CD8- (CD4SP) thymocytes in itk-/- mice also develop as Eomesodermin+ innate T cells. These Eomes+ innate CD4+ T cells are CD44high, CD62Lhigh, CD122+, and CXCR3+ (Atherly et al., 2006b; Broussard et al., 2006; Dubois et al., 2006; Weinreich et al., 2010). Surprisingly, neither CD4SP nor CD8SP innate thymocytes in itk-/- mice are dependent on γδ T cells for their development as was previously hypothesized (Alonzo and Sant'Angelo, 2011). Instead, both subsets of innate itk-/- T cells require the presence of a novel PLZF-expressing, SAP-dependent thymocyte population that is essential for the conversion of conventional CD4+ and CD8+ T cells into Eomesodermin-expressing innate T cells with a memory phenotype. This novel subset of PLZF-expressing SAP-dependent innate T cells preferentially home to the spleen and mesenteric lymph nodes and have a restricted TCR repertoire. Thus, we have christened this subset as CD4+ PLZF + MAIT-like cells. We have characterized multiple subsets of innate T cells that expand in the absence of Itk. Therefore, we were interested in how innate T cells respond to infection. Although Itk KO mice have defects in cytolytic function and cytokine production during an acute infection, these mice are able to clear viral infections (Atherly et al., 2006a; Bachmann et al., 1997). Hence, we hypothesized that Itk-deficient memory CD8+ T cells would be able to provide protection upon a challenge infection. Conversely, we found this not to be true although Itk-deficient memory CD8+ T cells were present in similar frequencies and cell numbers as WT memory CD8+ T cells at 42 days post-infection. Furthermore, Itk-deficient memory CD8+ T cells were able to produce IFNγ and exert cytolytic function upon stimulation. Although the function of Itk-deficient memory CD8+ T cells appeared to be intact, we found that these cells were unable to expand in response to a challenge infection. Remarkably, conventional memory CD8+ T cells lacking Itk were able to expand and form protective memory responses upon challenge. Thus, the inability of Eomes+ innate CD8+ T cells to form protective memory responses does not appear to be intrinsic to cells deficient in Itk. This thesis is divided into six major chapters. The first chapter will provide an introduction to T cell development and the role of Itk in T cell development. Additionally, it will introduce a variety of innate T cell subsets that will be discussed throughout this thesis and will provide an overview of CD4+ and CD8 + T cell differentiation during infection. This section will explain the role of Itk in CD4+ helper T cell differentiation and describe how Itk-deficient CD8+ T cells respond to acute infection. The introduction will also discuss the generation of conventional memory CD8+ T cells. The second chapter will provide the details of the experimental procedures used in this thesis. The third chapter will describe the characterization and development of Eomes+ innate CD4+ T cells that develop in the absence of Itk. Additionally, this chapter will address the subset of PLZF+ innate T cells that induce the expression of Eomes in innate T cells. The fourth chapter will further characterize and explore the development of itk-/- CD4+ PLZF+ MAIT-like T cells. The fifth chapter will examine the role of Eomes + innate CD8+ T cells in protective memory responses. Chapters three through five will display work that is in preparation to be submitted to a peer-reviewed journal. The sixth chapter will discuss the results of this thesis and their implications.
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Mugyenyi, Cleopatra Kama. "The acquisition and maintenance of antibodies to merozoite antigens of Plasmodium falciparum and their role in protective immunity to malaria." Thesis, Open University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522224.
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Cheramie, Martin N. "Investigations into Mycobacterium marinum Interacting and Crossing Fish Gut Epithelia| Evidence for Inducing a Protective Gut Mucosal Immunity by a Live Vaccine Candidate." Thesis, University of Louisiana at Lafayette, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=1585851.
Full textAbstract:
Mycobacterium marinum is an established surrogate pathogen for Mycobacterium tuberculosis because of M. marinum 's strong conservation of thousands of orthologous genes, lower risk, lower financial burden to researchers, and similar pathology in fish. This pathogen causes TB-like chronic disease in a wide variety of fish species and can mount superficial infection of human tissues. As in human TB, the microbe grows within the host macrophages, can mount life-long chronic infections, and produces granulomatous lesions in target organs. One of the fish species known to manifest chronic "fish TB" is the small laboratory fish, Japanese medaka (Oryzias latipes). Recently, our lab documented the progression of the bacterium from the lumen of the gut to underlying tissues and to target organs to mount infection. Since the bacterium can be observed crossing the epithelia to mount infection, I tested to see if mucosal immunity against a wild-type challenge could be induced by initially priming the fish to a live, attenuated vaccine strain. This thesis demonstrates that inoculation by ingestion is an efficient mode by which medaka can become infected and vaccinated with M. marinum. Furthermore, my thesis shows that orally vaccinating fish with a live, attenuated strain indeed provides protection in the gut, liver, and kidney against a virulent, wild-type challenge.
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Jobsri, Jantipa. "Induction of protective antigen-specific anti-tumour immunity using vaccines incorporating immunoenhancing properties of the coat protein from the potato virus X (PVX)." Thesis, University of Southampton, 2010. https://eprints.soton.ac.uk/362530/.
Full textAbstract:
DNA fusion vaccines encoding the idiotypic (Id) single chain variable fragments of B-cell malignancies fused to the potato virus X coat protein (PVXCP) were shown to enhance anti Id antibody and T-cell responses which resulted in protection in lymphoma and myeloma models. I further explored the use of PVXCP to enhance induction of anti -tumour immunity. The aims of this study were to generate two types of Id tumour vaccines against the BCL1 lymphoma, a multimeric Id-PVXCP fusion protein and a PVX particle displaying Id antigen, and to compare their performance with the DNA fusion vaccine. The multimeric fusion protein vaccine was produced in plants using the HyperTrans expression system. Three constructs which directed expression to the cytoplasm, for retention in the endoplasmic reticulum (ER) and for secretion were tested. The construct that directed the fusion protein to retain in the ER provided high protein expression and was used for further studies. The fusion protein was purified by antibody affinity chromatography and size exclusion. ELISA confirmed the integrity of the expressed protein and protein multimerisation was shown by transmission electron microscopy (TEM). This vaccine induced both anti-Id and anti-PVXCP antibody responses in mice to the levels comparable to the DNA vaccine and it provided protection against the lymphoma challenge. The plant viral particle (PVP) Id vaccine was produced by linking BCL]IgG to PVX via biotin-streptavidin. The PVP vaccine induced both anti-Id and anti-PVXCP antibodies to significantly higher levels than the DNA vaccine. PVP provided protection to the levels comparable to the DNA vaccine. The PVP vaccine also induced cellular responses as high numbers of PVXCP-specific IFN-y and IL-2 secreting cells were detected. In vivo PVX bound to CD 11 c + dendritic cells (DCs) and induced activation of all CD 11 c + DC subsets as determined by up-regulation of activation markers. PVX-activated DCs also changed their cytokine, chemokine and chemokine receptor expression profiles toward activated DC phenotypes. These data suggest that PVX enhanced immunity to the linked tumour antigen with the involvement of T cells and DCs. The feasibility of genetically linking BCL] scFv to PVX was also determined. BCLI scFv sequence was fused to the N-terminus of PVXCP sequence and inserted into a PVX-based vector to enable expression of the chimeric viral particle (CVP) in plants. CVP was assembled in plants as judged by the ability to infect host plants both locally and systemically. The CVP RNA and proteins (both fusion protein and PVXCP) were detected in all infected leaves. BCLI scFv on the CVP surface was detected by TEM with goldlabelled anti -BCLI antibody. However, low amount of CVP was obtained and therefore this vaccine production strategy requires further optimisation.
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Musasia, Fauzia Khagai [Verfasser], and Michael [Akademischer Betreuer] Lanzer. "Antibody mediated clearance of ring-infected erythrocytes as a mechanism of protective immunity against Plasmodium falciparum malaria / Fauzia Khagai Musasia ; Betreuer: Michael Lanzer." Heidelberg : Universitätsbibliothek Heidelberg, 2020. http://d-nb.info/1206347864/34.
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Roy, Eleanor. "Response of dendritic cells to Mycobacterium tuberculosis infection and the induction of protective immunity using dendritic cells infected with an auxotrophic mutant of M. tuberculosis." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1446801/.
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Mycobacterium tuberculosis, the aetiological agent of tuberculosis, is an intracellular pathogen commonly infecting macrophages, and has also been shown to infect dendritic cells (DC). As DC are particularly effective antigen-presenting cells, it is likely that they play a principle role in initiating anti-mycobacterial T cell responses. This work investigates the activation of DC in response to M. tuberculosis infection using murine bone marrow-derived DCs, generated in the presence of granulocyte- macrophage colony-stimulating factor (GM-CSF). It was found that both unsorted DC populations and those sorted on CD11c+, were capable of supporting the survival and replication of wild type M. tuberculosis (H37Rv) in a manner similar to that observed in macrophages. Mycobacterial infection was found to be sufficient to activate the DC populations, particularly CD11c+ DC, to acquire a mature phenotype, as measured by cytokine production and expression of costimulatory and antigen presentation molecules on the cell surface. Further study showed that mycobacteria-infected DC could prime protective immunity in an experimental model of murine tuberculosis. This was carried out using a lysine auxotroph of M. tuberculosis. Infected DC were used to vaccinate syngeneic or allogeneic mice. Protection against challenge with wild type M. tuberculosis was observed in both cases, suggesting that recipient antigen-presenting cells crosspresented mycobacterial antigen from donor DC to induce a protective immune response. A similar protective response was observed on using a xenogeneic model, in which infected murine DC were used to vaccinate guinea pigs. Both CD4+ and CD8+ T cells harvested from spleens of vaccinated mice, showed specific production of interferon-y in response to mycobacterial antigen, indicating that crosspresentation by recipient antigen-presenting cells results in the effective priming of mycobacteria-specific T cells in vivo.
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Alaofi, Youssef Ali D. "The impact of the classical, lectin and alternative pathways of complement activation on protective immunity against Streptococcus pneumoniae infection following vaccination with established pneumococcal vaccines." Thesis, University of Leicester, 2017. http://hdl.handle.net/2381/42421.
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Streptococcus pneumoniae (S. pneumoniae) is a pathogen that can cause infectious disease, such as meningitis, septicaemia and pneumonia. As part of innate immunity, the complement system plays a major role in the immune response to S. pneumoniae. Given this, the aim was to determine the impact of selective deficiencies for classical, lectin and alternative pathways of complement activation on vaccination response using pneumococcal polysaccharide vaccines. All results were achieved using CRM197 (a non-toxic mutant of diphtheria toxin), which elicited a different immune response in comparison to pneumococcal polysaccharide vaccines (PneumovaxII and Prevenar13). WT mice, C1q-/-, MASP-2-/- and fB-/- mice were immunised subcutaneously or intraperitoneally (s.c./i.p.) with either 20μg of CRM197, 1μg of PneumovaxII (pneumococcal polysaccharide vaccine) or 1μg of Prevenar13 (pneumococcal polysaccharide conjugate vaccine). Mice received a single or three spaced dose of CRM197, PneumovaxII or Prevenar13 and then a final booster one week before the end of the experiment. Blood samples were taken at different time points and all mice responded with high antibody titres to CRM197, PneumovaxII and Prevenar13; showing, an increase in antibody response to CRM197 immediately after the third immunisation and after the first immunisation for PneumovaxII and Prevenar13. This suggested that the antibody response to CRM197 was independent from the presence or absence of C1q (classical pathway) and MASP-2 (lectin pathway), but was increased in C1q deficient mice for PneumovaxII and was completely independent for Prevenar13. Imperative to the effective treatment of pneumococcal infections, this project significantly aided in the understanding of the complement system and has highlighted the importance of activation pathways in protective responses. Overall, PneumovaxII showed that the classical complement pathway might play a negative regulatory role, whilst the lectin and the alternative pathways are involved in the positive regulation and minor positive regulation of immune responses.
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Barker, Christopher Jon. "Identification and characterization of novel candidates for a vaccine against chlamydial genital tract infection." Thesis, Queensland University of Technology, 2007. https://eprints.qut.edu.au/16487/1/Christopher_Barker_Thesis.pdf.
Full textAbstract:
Chlamydia trachomatis is a human pathogen of the genital tract and ocular epithelium. It is an obligate intracellular parasite with a unique biphasic development cycle. C.trachomatis infection is the most common bacterial sexually transmitted disease in industrialized nations. Its ability to cause chronic disease makes it a serious economic burden and health threat to developed and developing countries. Although treatable, approximately 70% of C.trachomatis infections are asymptomatic, potentially leading to the development of chronic sequelae. Furthermore, chlamydial genital tract infection has been associated with an increased risk of cervical cancer and human immunodeficiency virus infection. Consequently, the development of an efficacious vaccine is the most convenient, potentially reliable and cost effective option to control chlamydial infection and disease complications.
Anti-chlamydial protective immunity is essentially mediated by a T helper, type 1 (Th1), response that is dependent upon the presentation of antigen via major histocompatibility (MHC) class II molecules. While antibody secreting cells are not critical components of the primary effector response, they have been shown to be important for clearance of re-infection. Thus an ideal vaccine would be one capable of inducing both a strong Th1 T cell response and a strong mucosal antibody response. Currently there are very few efficacious vaccine candidates that have been identified and characterized. More specifically, there is only a limited number of known T cell antigens processed and presented by the human leukocyte antigen (HLA) class II molecules. This type of antigen is going to be essential to the development of an efficacious chlamydial vaccine.
In this study we have identified a number of unique vaccine candidates using a novel in silico approach. In an attempt to overcome HLA polymorphism the whole chlamydial genome was screened for proteins containing epitopes predicted to bind multiple HLA class II molecules (i.e. predicted ‘promiscuous’ T cell epitopes). A wide range of HLA class II molecules were used in this screen to identify vaccine antigens that could potentially offer broad and ethnically balanced population coverage. This analysis identified a number of novel targets and was validated by the identification of a known chlamydial T cell epitope.
A selection of these target proteins was cloned, expressed and purified. Recombinant protein was screened against serum samples from patients with both acute and chronic chlamydial infections. Two novel targets, hypothetical protein CT425 and ribonucleotide reductase small chain protein (NrdB) were identified as being immunoreactive.
The in vivo protective efficacy of NrdB was analyzed using a mouse model. CD4+ T cells were harvested from NrdB immunized mice and adoptively transferred to naïve mice, which were subsequently infected at the genital site. NrdB immunization was found to confer a CD4+ T cell driven degree of protection similar to that seen with CD4+ T cells primed from a live challenge. The adjuvants and route of immunization used ensured immunological responses were initiated at both the systemic and local sites of infection. Immunization elicited a predominant Th1 response with primed T cells producing high levels of interferon gamma, an essential requirement for the development of an efficacious chlamydial vaccine. Furthermore, high titres of antigen specific IgG and IgA were produced following immunization, with sera derived antibodies demonstrating neutralization properties. NrdB is a highly conserved chlamydial protein with an essential role in the replication of chlamydiae and could play a central role in a multi-subunit vaccine against chlamydial genital tract infections.
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Barker, Christopher Jon. "Identification and characterization of novel candidates for a vaccine against chlamydial genital tract infection." Queensland University of Technology, 2007. http://eprints.qut.edu.au/16487/.
Full textAbstract:
Chlamydia trachomatis is a human pathogen of the genital tract and ocular epithelium. It is an obligate intracellular parasite with a unique biphasic development cycle. C.trachomatis infection is the most common bacterial sexually transmitted disease in industrialized nations. Its ability to cause chronic disease makes it a serious economic burden and health threat to developed and developing countries. Although treatable, approximately 70% of C.trachomatis infections are asymptomatic, potentially leading to the development of chronic sequelae. Furthermore, chlamydial genital tract infection has been associated with an increased risk of cervical cancer and human immunodeficiency virus infection. Consequently, the development of an efficacious vaccine is the most convenient, potentially reliable and cost effective option to control chlamydial infection and disease complications.
Anti-chlamydial protective immunity is essentially mediated by a T helper, type 1 (Th1), response that is dependent upon the presentation of antigen via major histocompatibility (MHC) class II molecules. While antibody secreting cells are not critical components of the primary effector response, they have been shown to be important for clearance of re-infection. Thus an ideal vaccine would be one capable of inducing both a strong Th1 T cell response and a strong mucosal antibody response. Currently there are very few efficacious vaccine candidates that have been identified and characterized. More specifically, there is only a limited number of known T cell antigens processed and presented by the human leukocyte antigen (HLA) class II molecules. This type of antigen is going to be essential to the development of an efficacious chlamydial vaccine.
In this study we have identified a number of unique vaccine candidates using a novel in silico approach. In an attempt to overcome HLA polymorphism the whole chlamydial genome was screened for proteins containing epitopes predicted to bind multiple HLA class II molecules (i.e. predicted ‘promiscuous’ T cell epitopes). A wide range of HLA class II molecules were used in this screen to identify vaccine antigens that could potentially offer broad and ethnically balanced population coverage. This analysis identified a number of novel targets and was validated by the identification of a known chlamydial T cell epitope.
A selection of these target proteins was cloned, expressed and purified. Recombinant protein was screened against serum samples from patients with both acute and chronic chlamydial infections. Two novel targets, hypothetical protein CT425 and ribonucleotide reductase small chain protein (NrdB) were identified as being immunoreactive.
The in vivo protective efficacy of NrdB was analyzed using a mouse model. CD4+ T cells were harvested from NrdB immunized mice and adoptively transferred to naïve mice, which were subsequently infected at the genital site. NrdB immunization was found to confer a CD4+ T cell driven degree of protection similar to that seen with CD4+ T cells primed from a live challenge. The adjuvants and route of immunization used ensured immunological responses were initiated at both the systemic and local sites of infection. Immunization elicited a predominant Th1 response with primed T cells producing high levels of interferon gamma, an essential requirement for the development of an efficacious chlamydial vaccine. Furthermore, high titres of antigen specific IgG and IgA were produced following immunization, with sera derived antibodies demonstrating neutralization properties. NrdB is a highly conserved chlamydial protein with an essential role in the replication of chlamydiae and could play a central role in a multi-subunit vaccine against chlamydial genital tract infections.
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Brenneman, Karen Elaine. "Investigation and characterization of the enhanced humoral response following immunization with the lethal and edema toxins of bacillus anthracis." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1174317572.
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O’Meara, Connor Patrick. "The development of an effective vaccine against Chlamydia : utilisation of a non-toxic mucosal adjuvant to generate a protective mucosal response." Thesis, Queensland University of Technology, 2012. https://eprints.qut.edu.au/61614/1/Connor_O%27Meara_Thesis.pdf.
Full textAbstract:
Chlamydia is responsible for a wide range of diseases with enormous global economic and health burden. As the majority of chlamydial infections are asymptomatic, a vaccine has greatest potential to reduce infection and disease prevalence. Protective immunity against Chlamydia requires the induction of a mucosal immune response, ideally, at the multiple sites in the body where an infection can be established. Mucosal immunity is most effectively stimulated by targeting vaccination to the epithelium, which is best accomplished by direct vaccine application to mucosal surfaces rather than by injection. The efficacy of needle-free vaccines however is reliant on a powerful adjuvant to overcome mucosal tolerance. As very few adjuvants have proven able to elicit mucosal immunity without harmful side effects, there is a need to develop non-toxic adjuvants or safer ways to administered pre-existing toxic adjuvants.
In the present study we investigated the novel non-toxic mucosal adjuvant CTA1-DD. The immunogenicity of CTA1-DD was compared to our "gold-standard" mucosal adjuvant combination of cholera toxin (CT) and cytosine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN). We also utilised different needle-free immunisation routes, intranasal (IN), sublingual (SL) and transcutaneous (TC), to stimulate the induction of immunity at multiple mucosal surfaces in the body where Chlamydia are known to infect. Moreover, administering each adjuvant by different routes may also limit the toxicity of the CT/CpG adjuvant, currently restricted from use in humans. Mice were immunised with either adjuvant together with the chlamydial major outer membrane protein (MOMP) to evaluate vaccine safety and quantify the induction of antigen-specific mucosal immune responses. The level of protection against infection and disease was also assessed in vaccinated animals following a live genital or respiratory tract infectious challenge.
The non-toxic CTA1-DD was found to be safe and immunogenic when delivered via the IN route in mice, inducing a comparable mucosal response and level of protective immunity against chlamydial challenge to its toxic CT/CpG counterpart administered by the same route. The utilisation of different routes of immunisation strongly influenced the distribution of antigen-specific responses to distant mucosal surfaces and also abrogated the toxicity of CT/CpG. The CT/CpG-adjuvanted vaccine was safe when administered by the SL and TC routes and conferred partial immunity against infection and pathology in both challenge models. This protection was attributed to the induction of antigen-specific pro-inflammatory cellular responses in the lymph nodes regional to the site of infection and rather than in the spleen. Development of non-toxic adjuvants and effective ways to reduce the side effects of toxic adjuvants has profound implications for vaccine development, particularly against mucosal pathogens like Chlamydia. Interestingly, we also identified two contrasting vaccines in both infection models capable of preventing infection or pathology exclusively. This indicated that the development of pathology following an infection of vaccinated animals was independent of bacterial load and was instead the result of immunopathology, potentially driven by the adaptive immune response generated following immunisation. While both vaccines expressed high levels of interleukin (IL)-17 cytokines, the pathology protected group displayed significantly reduced expression of corresponding IL-17 receptors and hence an inhibition of signalling. This indicated that the balance of IL-17-mediated responses defines the degree of protection against infection and tissue damage generated following vaccination. This study has enabled us to better understand the immune basis of pathology and protection, necessary to design more effective vaccines.
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Kimoto, Terumi. "Differences in gamma interferon production induced by listeriolysin O and ivanolysin O result in different levels of protective immunity in mice infected with Listeria monocytogenes and Listeria ivanovii." Kyoto University, 2003. http://hdl.handle.net/2433/148467.
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Evert, Benjamin J. "Applications of polyhydroxy butyrate bead technology." Thesis, Griffith University, 2022. http://hdl.handle.net/10072/411889.
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Recent research into bioengineered polyhydroxy butyrate (PHB) bead technology has resulted in the ability to generate functional polyester nanoparticles and materials with diverse applications across many fields of science. Through protein engineering and by hijacking Escherichia coli as a high yielding cell factory the Rehm lab group has been able to generate hundreds of PHB beads coated in various target proteins for multiple applications. The possible applications of this technology are only limited by our own ideas for targets which can be applied to the PHB bead technology. PHB beads coated in antigenic proteins have been previously developed and used as particulate vaccines in various animal trials. Several other PHB beads have been developed which had demonstrated applications in enzyme immobilisation, bioseperation, diagnostic imaging, drug delivery and bioremediation. The application of PHB bead technology depends on the target proteins designed to coat the surface of the beads. Here I continue exploring novel applications of PHB bead technology bygenerating several novel PHB beads with applications as particulate vaccines and a bioseperation resin which are outlined in this thesis. There are four separate projects highlighted in this thesis, all focused on PHB beads, but each with a different focus and overall aim. The first project I generated several malaria vaccine candidates (Chapter 3 and 4) with the overall aim to generate promising malaria vaccine candidates and highlight the benefits of PHB bead technology as well as explore alternative methods for coating PHB beads with antigenic proteins. Two of the vaccines generated strong immune responses in sheep animal trials and antibodies which were able to inhibit traversal of malaria sporozoites into human hepatocytes. Another vaccine showed promising results in a rat animal trial and will be explored further by future students. The results from this project resulted in one first author manuscript currently submitted for publication and future work to be continued by other students. The second project I generated a SARS-CoV-2 vaccine candidate by using an alternative method of coating PHB beads with the target antigen (Chapter 5). The aim was to fill the unmet need for a rapidly adaptable, scalable, and economically viable vaccine platform technology which could combat the ongoing pandemic and additionally highlight the benefits of a new method for attaching antigenic proteins to PHB beads. This vaccine candidate was combined with six others in two animal trails All six vaccines showed a strong and specific immune response in the first animal study. The two best performing vaccines were assessed by a second animal trial and demonstrated protective immunity in hamsters. The results from this project resulted in a second author manuscript currently submitted for publication.The third project I designed three chikungunya vaccine candidates (Chapter 6). We aimed to generate a chikungunya vaccine candidate that generated a strong and functional immune response and again highlight the benefits of a new method for attaching target proteins to PHB beads. However due to experimental complications and time constraints I was only able to generate one of the three vaccine candidates. This vaccine candidate was characterised and assessed for suitability to be taken into animal trials. The work from this project will be continued by future students. The vaccine candidates will eventually be tested in animal trials. The fourth project I generated three novel bioseperation resins using PHB bead technology (Chapter 7). We aimed to generate a bioseperation resin that was easy to use, improved on current technologies and could be a valuable tool used by scientist in the molecular biology field. The physical and chemical properties of the resin was characterised. The ability to purify three structurally and functionally diverse target proteins was assessed, and the performance was compared to the commonly used His-tag affinity resin. We found that the resin was able to purify the target proteins from complex mixtures even at concentrations not detectable by SDS-PAGE analysis. Furthermore, the resins performance was comparable to the traditionally used His-Tag affinity resin with several distinct advantages. The results from this work resulted in a first author publication. Overall, the work presented in this thesis significantly contributes to the field by furthering the applications and possible applications of bioengineered PHB bead technology. Each of these chapters demonstrates a unique application of PHB bead technology that had previously not been explored. Furthermore, by providing an alternate way of attaching target proteins to PHB beads we open the door to future projects that previously could not be done due to the limitations of the current technology.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Environment and Sc
Science, Environment, Engineering and Technology
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Masic, Anita [Verfasser], and Heidrun [Akademischer Betreuer] Moll. "Signaling via Interleukin-4 Receptor alpha chain during dendritic cell–mediated vaccination is required to induce protective immunity against Leishmania major in susceptible BALB/c mice / Anita Masic. Betreuer: Heidrun Moll." Würzburg : Universitätsbibliothek der Universität Würzburg, 2013. http://d-nb.info/1031379762/34.
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VanCott, John Louis. "Protective immunity against transmissible gastroenteritis virus (TGEW) : enumeration of antibody-secreting cells and identification of mononuclear cell surface markers in systemic and mucosal lymphoid tissues of young pigs exposed to TGEV... /." The Ohio State University, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487842372895095.
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