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Modulation of the allergen-specific Tcell responseGardner, Leanne M. (Leanne Margaret), 1977- January 2003 (has links)
Abstract not available
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Pseudomonas aeruginosa : development of a mucosal vaccine for respiratory infectionThomas, Linda D., n/a January 2001 (has links)
Pseudomonas aeruginosa (P. aeruginosa) is a frequently isolated pathogen that
causes septicaemia and chronic respiratory infection. It exhibits a higher
mortality rate than other gram-negative bacteria and the need for effective
immunotherapy is emphasised by the frequency of antibiotic resistance
associated with this organism. Mucosal immunisation with a whole killed cell P.
aeruginosa vaccine has previously demonstrated a significant immune response
in both rodent studies and human trials. This study is a continuation of that
research, with the major goal being the identification of a purified protein antigen
that could form the basis of a mucosal vaccine against P. aeruginosa.
Specifically, the aims of this study were the development of purification
protocols for the isolation of previously untested protein antigens, assessment of
the efficacy of these antigens to enhance bacterial clearance in an animal model
of acute respiratory infection, determination of the immune parameters that are
associated with the resolution of P. aeruginosa respiratory infection and finally,
cloning of an identified antigen which demonstrated vaccine efficacy.
Protocols were established to isolate proteins for use as antigens in immune
response studies. The proteins purified in this study were Pa 13, Azurin, acyl
carrier protein (ACP), Amidase, Aminopeptidase, KatA and Pa70. These proteins
were used to immunise rats by intestinal intra-Peyer's patch (IPP) inoculation and
intratracheal (IT) boost. The immunisation protocol employed was designed to
target mucosal antigen-specific immune responses where the route of
immunisation, Peyer's patch (PP) intestinal inoculation, is akin to the oral
delivery of antigens to the gut-associated lymphoid tissue (96).
Investigations of a previously uncharacterised antigen, Pa60, later identified this
protein as the P. aeruginosa catalase, KatA. This study demonstrated enhanced
bacterial clearance of both homologous and heterologous challenge following
immunisation with KatA. The level of clearance demonstrated by KatA was
promising when compared to that of killed whole cell immunisation. KatA was
cloned and studies with the recombinant protein showed enhanced bacterial
clearance commensurate with that of the native protein.
Immunisations with other proteins identified four additional antigens which
enhanced bacterial clearance; Pa13, Pa40, Pa45 and Pa70. Amino acid sequence
analysis indicated that Pa13 may be a novel protein, whereas Pa40 was
determined to be amidase and Pa45, aminopeptidase. Pa70 was not successfully
sequenced. These proteins were effective in significantly enhancing bacterial
clearance of homologous P. aeruginosa challenge. For KatA, Pa13 and Pa70,
clearance was associated with a marked phagocytic cell recruitment. In contrast,
amidase and aminopeptidase demonstrated clearance with a minimal cellular
response. Proteins; azurin and ACP were non-protective, failing to clear a live P
aeruginosa challenge. Analysis of the antigen-specific responses of these nonprotective
proteins and comparison with those antigens which enhanced bacterial
clearance were used to determine factors that may contribute to the resolution of
an acute pulmonary infection.
The study has demonstrated that mucosal immunisation using purified protein
antigens can enhance the clearance of pulmonary infection with P. aeruginosa. It
has also contributed to the understanding of immune responses to newfound
antigens of P. aeruginosa and identified antigen-specific responses which
confirm their potential as vaccine candidates.
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The Role of CD8+ T Cell Phenotype and Cytotoxicity on Cancer ImmunotherapyStark, Felicity 03 October 2011 (has links)
Cancer vaccines can fail despite the induction of large numbers of CD8+ T cells. Two categories of memory CD8+ T cells have been defined; central memory (TCM, IL-7RαhighCD44highCD62Lhigh) and effector memory (TEM, IL-7RαhighCD44highCD62Llow). It is clear that the memory phenotype of CD8+ T cells can affect vaccine potential; however methods to augment a beneficial phenotype are not clear. I have compared three vaccine delivery systems: Listeria monocytogenes, Salmonella enterica serovar Typhimurium and the particulate liposomal adjuvant, archaeosomes, for their efficacy to protect against murine melanoma. My study revealed that the anti-tumour response is strongly influenced by the kinetics, phenotype, and lymph node homing potential of CD8+ T cells.
Listeria monocytogenes-ovalbumin (LM-OVA) induced TCM cells were adept at long lasting protection against B16-OVA melanoma due to their increased homeostatic and antigen-induced proliferation, interleukin-2 production, and ability to extravasate into tumour draining lymph nodes. Conversely, although Salmonella Typhimurium-ovalbumin (ST-OVA) induced TEM, produced IFN-γ, and killed target cells, this was insufficient for long-term tumour protection.
Selectin-ligand engagements of TCM cells influenced their homing potential and efficacy against murine melanoma. Fucosyltransferase deficient (FtDKO) mice, lacking functional selectin ligands, were vaccinated with LM-OVA; despite the activation of cytotoxic CD8+ T cells, there was a reduced protection against murine melanoma compared to wild-type. FtDKO CD8+ T cells exhibited reduced extravasation into FtDKO lymph nodes compared to wild-type. Additionally, fewer FtDKO CD8+ T cells compared to wild-type migrated into tumour sites.
Archaeosome vaccination was used to compare the influence of CD8+ T cell quantity versus phenotype. Single or multiple therapeutic vaccinations with archaeosome-OVA yielded transient melanoma tumour protection, despite an increased frequency of circulating and tumour infiltrating CD8+ T cells. This correlated with increased expression of Program death receptor-1 (PD-1) on CD8+ T cells and induction of regulatory T cells. Prophylactic archaeosome-OVA vaccination resulted in a maximal frequency of antigen-specific CD8+ T cells of ~50-60 % with just three injections, and ~50 % of the mice were of mice were afforded long-term tumour protection (> 90 days).
Overall, my study shows that the choice of vaccine adjuvant and/or vector can profoundly influence CD8+ T cell quality and cancer vaccine efficacy.
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Purified Protein Derivative (PPD) Tuberculin as a Biological Response Modifier: I. Suppression of Tumor Markers by Intravenous Administration of PPDYOSHII, SAIJI, NAKASHIMA, IZUMI, ANDO, KOICHI, AOKI, HIIZU, KATO, KATSUYA, IINUMA, MASAO 03 1900 (has links)
No description available.
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Development of a Model to Study the Abscopal Effect: Combining Image-guided Radiation Therapy and Immunotherapy in Cancer TreatmentMoretti, Amanda 12 January 2011 (has links)
Distant metastases are a limiting factor in cancer patient survival as they are least accessible to conventional therapies. Effective therapy should treat primary tumours and metastatic disease. Use of image-guided radiation therapy (IGRx) enables high doses of radiation to be delivered for better tumour control while minimizing toxicity to healthy tissues. Systemic effects on distant non-irradiated tissues have been observed following IGRx. This phenomenon, termed the abscopal effect, is hypothesized to be mediated by the immune system. The inflammatory milieu generated following IGRx may activate immune cells to mount specific anti-tumour responses. The work described in this thesis aims to develop a model to study the abscopal effect, and evaluate the potential of combining IGRx and immunotherapy to enhance such distant tumour killing. Results from these studies may have clinical implications, where a combined IGRx and immunotherapy approach may prove useful in eliciting regression of local tumours and distant metastases.
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Development of a Model to Study the Abscopal Effect: Combining Image-guided Radiation Therapy and Immunotherapy in Cancer TreatmentMoretti, Amanda 12 January 2011 (has links)
Distant metastases are a limiting factor in cancer patient survival as they are least accessible to conventional therapies. Effective therapy should treat primary tumours and metastatic disease. Use of image-guided radiation therapy (IGRx) enables high doses of radiation to be delivered for better tumour control while minimizing toxicity to healthy tissues. Systemic effects on distant non-irradiated tissues have been observed following IGRx. This phenomenon, termed the abscopal effect, is hypothesized to be mediated by the immune system. The inflammatory milieu generated following IGRx may activate immune cells to mount specific anti-tumour responses. The work described in this thesis aims to develop a model to study the abscopal effect, and evaluate the potential of combining IGRx and immunotherapy to enhance such distant tumour killing. Results from these studies may have clinical implications, where a combined IGRx and immunotherapy approach may prove useful in eliciting regression of local tumours and distant metastases.
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The Role of CD8+ T Cell Phenotype and Cytotoxicity on Cancer ImmunotherapyStark, Felicity 03 October 2011 (has links)
Cancer vaccines can fail despite the induction of large numbers of CD8+ T cells. Two categories of memory CD8+ T cells have been defined; central memory (TCM, IL-7RαhighCD44highCD62Lhigh) and effector memory (TEM, IL-7RαhighCD44highCD62Llow). It is clear that the memory phenotype of CD8+ T cells can affect vaccine potential; however methods to augment a beneficial phenotype are not clear. I have compared three vaccine delivery systems: Listeria monocytogenes, Salmonella enterica serovar Typhimurium and the particulate liposomal adjuvant, archaeosomes, for their efficacy to protect against murine melanoma. My study revealed that the anti-tumour response is strongly influenced by the kinetics, phenotype, and lymph node homing potential of CD8+ T cells.
Listeria monocytogenes-ovalbumin (LM-OVA) induced TCM cells were adept at long lasting protection against B16-OVA melanoma due to their increased homeostatic and antigen-induced proliferation, interleukin-2 production, and ability to extravasate into tumour draining lymph nodes. Conversely, although Salmonella Typhimurium-ovalbumin (ST-OVA) induced TEM, produced IFN-γ, and killed target cells, this was insufficient for long-term tumour protection.
Selectin-ligand engagements of TCM cells influenced their homing potential and efficacy against murine melanoma. Fucosyltransferase deficient (FtDKO) mice, lacking functional selectin ligands, were vaccinated with LM-OVA; despite the activation of cytotoxic CD8+ T cells, there was a reduced protection against murine melanoma compared to wild-type. FtDKO CD8+ T cells exhibited reduced extravasation into FtDKO lymph nodes compared to wild-type. Additionally, fewer FtDKO CD8+ T cells compared to wild-type migrated into tumour sites.
Archaeosome vaccination was used to compare the influence of CD8+ T cell quantity versus phenotype. Single or multiple therapeutic vaccinations with archaeosome-OVA yielded transient melanoma tumour protection, despite an increased frequency of circulating and tumour infiltrating CD8+ T cells. This correlated with increased expression of Program death receptor-1 (PD-1) on CD8+ T cells and induction of regulatory T cells. Prophylactic archaeosome-OVA vaccination resulted in a maximal frequency of antigen-specific CD8+ T cells of ~50-60 % with just three injections, and ~50 % of the mice were of mice were afforded long-term tumour protection (> 90 days).
Overall, my study shows that the choice of vaccine adjuvant and/or vector can profoundly influence CD8+ T cell quality and cancer vaccine efficacy.
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MFG-E8 Blockade Enhances Tumor Immunity in a Murine Breast Cancer ModelDraganov, Dobrin Draganov January 2012 (has links)
Milk fat globule - epidermal growth factor - factor 8 protein (MFG-E8) is an important mediator of the tolerogenic functions of GM-CSF, and a dominant-negative RGE mutant augments the therapeutic potential of irradiated, GM-CSF-secreting tumor vaccines (GVAX) in the MFG-E8-negative B16 melanoma model. The frequent expression of MFG-E8 in various solid and hematological malignancies, however, prompted us to investigate the effect of the RGE mutant in a MFG-E8-positive transplantable breast tumor model. Here, we report that MFG-E8 blockade augmented anti-tumor humoral responses and modulated immune infiltrates at vaccination sites, which was associated with defective phagocytosis and clearance of apoptotic tumor cells. The RGE mutant enhanced the therapeutic potential of two irradiated, GM-CSF-secreting vaccines and improved protection correlated with augmented tumor-specific IgG1 and IgG2a antibody responses as well as increased ratios of T effectors to Tregs in TILs. These findings are consistent with the notion that MFG-E8 blockade potentiates anti-tumor responses through the preferential expansion of effector over regulatory T cells. Our data also validate the use of the RGE mutant to achieve therapeutically effective MFG-E8 blockade even in the context of tumors and vaccines that express high levels of endogenous MFG-E8.
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Chronic hepatitis C infection: diagnosis, fibrosis progression and interferon therapyHui, Chee-kin., 許志堅. January 2003 (has links)
published_or_final_version / abstract / toc / Medicine / Master / Doctor of Medicine
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Activation of Immune System Function Against Cancer by Heat Shock ProteinsKislin, Kerri January 2006 (has links)
Chaperone proteins such as heat-shock proteins 70, 90 and 110, glucose-related protein 94 and calreticulin have been reported to be effective anti-tumor vaccines when purified from a tumor source. We have developed a procedure utilizing a free-solution-isoelectric focusing technique to obtain vaccines from tumor or normal tissue sources that are rich in multiple immunogenic chaperone proteins, called Chaperone-Rich Cell Lysate (CRCL). Tumor-associated peptides are presumed to be the currency of T-cell mediated anti-cancer immunity, and tumor-derived chaperone vaccines are believed to be purveyors of such peptides. As a novel anti-cancer strategy, we have examined the extent to which the peptide repertoire of CRCL can be manipulated. Here, we explored the concept of creating a designer CRCL, utilizing the adjuvant properties and the carrying capacity of CRCL to deliver exogenous antigenic peptides for DC-based presentation and ultimately demonstrate the anti-tumor efficacy of the designer vaccine in vivo. Designer CRCL allows for the development of personalized vaccines to those afflicted with cancer expressing known antigens.Growing evidence indicates that the stress response, specifically involving HSPs, has a profound impact on tumor immunogenicity. Enhancement of T-cell-mediated immunogenicity correlates with the expression of inducible heat shock protein 70 (iHSP70), the major heat-inducible member of the HSP70 family. In addition, studies have shown tumor-specific cell surface localization of iHSP70 correlates with an increased sensitivity to lysis mediated by human natural killer (NK) cells. Given these findings, investigating novel and effective means of modulating the heat shock response within tumor cells may bear great therapeutic potential and result in potent anti-tumor immune activity. Withaferin A (WA) is a compound isolated from the plant Withania somnifera that has been shown to induce a robust transcriptional heat shock response. In our studies, we found that WA treatment resulted in increased surface expression of iHSP70 in several tumor types leading to significant immunostimulatory effects. These findings indicated that WA-dependent modulation of the heat shock response may enhance tumor immunogenicity. Given the potent immunomodulatory and anti-tumor effects of WA as well as the adjuvanticity and specificity of peptide-complexed CRCL against tumors, these therapies individually have shown profound anti-cancer activity.
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