There is plenty of evidence from epidemiology studies supporting a link between certain components in the human diet and cancer incidence. It is estimated that 3-4 million annual cases of cancer could be prevented worldwide just by changing dietary habits. In parts of the world where vegetables and fruits constitute a large part of the diet, certain cancer incidences are markedly lower compared to Western countries. In particular, consumption of cruciferous vegetables is negatively associated with occurrence of certain cancers. One of the compounds from crucifers that is implicated in chemoprevention, is indole-3-carbinol(I3C), documented to inhibit tumor formation in several tissues in rodents, including the mammary tissue. I3C and is currently being evaluated in several clinical trials as a chemopreventive agent against breast cancer in humans. There are, however, some legitimate concerns regarding the use of Pure I3C since, depending upon conditions of administration, I3C can act as a promoter of hepatocarcinogenesis. Evidence is presented here that dietary I3C can promote and/or enhance liver tumor formation in rainbow trout (supporting earlier reports in literature) and the C57BL/6J mouse (enhancement in short-term pre-initiation exposure through lactational transfer, inhibition in a long-term post-initiation feeding study). I3C is also reported to promote in the rat liver model. A major concern associated with dietary I3C supplementation relates to its estrogenic effects as seen in trout and also its ability to induce certain cytochrome P-450s involved in procarcinogen activation. Biological effects of I3C are attributed to its acid condensation products. It was observed in this study that I3C acts through different mechanisms, including the Ah receptor-mediated and estrogenic pathways. Understanding of the role of I3C derivatives in beneficial and/or hazardous effects resulting from dietary exposure will be crucial in evaluating the promise of I3C as a chemoprevention agent. Questions pertaining to the risk/benefit of the use of dietary I3C supplementation for preventing estrogen-related diseases, without increasing the risk of promotion of hepatocarcinogenesis in humans, may depend on whether the mechanism(s) of action of I3C derivatives in humans is more like the adult mouse or the neonatal mouse, rat and trout. / Graduation date: 1998

published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Interleukin-17A (IL-17A)is an important pro-inflammatory cytokine that plays a critical role in host defenses against diverse pathogens. Studies have shown that IL-17Aplays protective role against sub-lethal H1 and H3 subtypes influenza infections, but it is unclear about the role of IL-17A in the highly pathogenic H5N1 and lethal H1N1 influenza virus infection. B cell is an important effector cell type in anti-influenza immunity. Although roles of B cell in influenza infection have been extensively investigated, it is unclear whether and how IL-17AregulatesB cell response during influenza infection. I examined the role of IL-17A against influenza infection by challengingIL-17A knockout (KO) and wild-type (WT) mice with highly pathogenic H5N1 and lethal H1N1 influenza viruses. Following challenge, IL-17AKO mice exhibited significantly lower survival rate, profoundly reduced body weight, more severe tissue damage and higher viral burden in the lung tissues. These evidences suggest that IL-17Aplays a protective role in lethal influenza infection. To study whether IL-17Amodulates B cell response against influenza, I found that both B-1a and B-2 cells were detected in the lung tissue and pulmonary draining lymph node, Mediastinal lymph node (MedLN),as early as 2days post-infection. Meanwhile, B-1a cells predominantly contributed to the early virus-specific IgM in the respiratory tract. However, virus-specific IgM markedly reduced in IL-17A KO mice when compared with WT controls. Adoptive transfer of B-1a cells or B-1a cell-derived antibodies conferred protection in IL-17A KO mice. These results demonstrate that IL-17A plays a critical role in modulating early antibody production of B-1a cells against lethal influenza infection. To further elucidate how IL-17A regulates B-1a cell response, I observed that B-1a cells migrated into MedLN and lung tissues during infection and underwent plasmacytic differentiation with increased antibody production in airways. IL-17A deficiency impaired these processes of B-1a cells, while intra-nasally instillation of IL-17A restored B-1a cell response by promoting both B-1a cell migration and plasmacytic differentiation. By inducing blimp-1 expression in B-1a cells in an NF-κB dependent pathway, IL-17A directly promoted plasmacytic differentiation of B-1a cells both in vivo and in vitro. Furthermore, chromatin immuno-precipitation analysis confirmed that NF-κB directly bound to the promoter of blimp-1 gene and promoted blimp-1 expression in B-1a cells following IL-17A stimulation. To determine the functional significance of IL-17A signaling in modulating B cell response against influenza infection, I first uncovered markedly reduced B cell response, predominantly B-1a cell response in IL-17A KO mice, showing reduced local migration and impaired plasmacytic differentiation in the early stage of infection. Next, intra-nasal administration of IL-17A into IL-17A KO mice significantly restored this B-1a cell response. Moreover, I detected expression of IL-17A receptor in B-1a cells. IL-17A treatment could promote antibody production from B-1a cells by inducing blimp-1 expression in an NF-κB dependent pathway. Taken together, these findings identify a novel role of IL-17A in actingas an immune modulator of B cell response against influenza infection, which will contribute to a fuller understanding of B cell biology and anti-viral response in host defense. / published_or_final_version / Pathology / Doctoral / Doctor of Philosophy

Graduate

published_or_final_version / Medicine / Master / Doctor of Medicine

In this thesis, mechanisms of immunoregulation by CD4$ sp+$ T cells during blood-stage P. chabaudi AS infection in C57BL/6 mice were studied. The kinetics of in vitro production of the Th1-derived cytokine, IFN-$ gamma$, versus the Th2-derived cyokines, IL-4, IL-5 and IL-10, by spleen cells as well as of polyclonal and malaria-specific antibodies in the sera were examined during infection using enzyme-linked immunosorbent assays. Upon antigenic stimulation, spleen cells were found to produce high levels of IFN-$ gamma$ several days prior to peak parasitemia, while high levels of IL-10 production occurred at the time of peak parasitemia followed by IL-4 and IL-5 later in infection. The levels of polyclonal IgG2a isotype were found to be increased during both the acute and chronic phases of infection, whereas the levels of polyclonal IgM, IgG1 and IgG2b isotypes were found to be increased only during the chronic phase of infection. High titers of malaria-specific IgG2a and IgG1 were detected during the primary as well as secondary infections. Investigation of in vitro proliferation of spleen cells to mitogens and malaria specific antigen revealed that the responses of splenic lymphocytes from infected mice to Con A, PHA and LPS were suppressed, with the most severe suppression occurring during the first 14 days post infection. Evidence is provided demonstrating that nitric oxide (NO) and prostaglandins (PG), products of activated macrophages, mediated suppression of lymphocyte proliferation in response to Con A and PHA, whereas only PG were found to suppress LPS-stimulated proliferation. In addition, NO was found to mediate suppression of proliferation of spleen cells from infected mice in response to parasite antigen. Taken together, results from these studies suggest that immune activation and immunosuppression occur simultaneously during blood-stage malaria with P. chabaudi AS infection in C57BL/6 mice. (Abstract shortened by UMI.)

Bibliography: leaves 170-206. / vi, 206 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / In T-dependent antibody responses, costimulator molecules provide contact-medited signals during interactions between T cells and B cells that regulate lymphocyte activation. This study investigated the hypothesis that costimulator molecules are differentially expressed on lymphocytes from neonates and young children compared with adults, contributing to limitations of T-dependent antibody responses in early life. Results suggest that lymphocytes from young children should be able to deliver and respond to costimulatory signals. The differences in lymphocyte expression of these costimulator molecules in young children are unlikely to fully account for limitations in humoral immunity in early life, and may even represent a specialised adaptation for this stage of immune development. / Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 2000

Includes bibliographical references (leaves 117-133). / v, 133 leaves, 5 leaves of photographic plates : ill. (some col.); 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Concerned with the family of genes that encode variant-specific surface proteins in the parasitic protzoon, Giardia. Specific goals were to identify and compare closely related genes, which may form subsets within the larger VSP gene family. / Thesis (Ph.D.)--Adelaide University, Dept. of Molecular Biosciences, 2001

xiv, 241, lix leaves : tables, graphs ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology, 1977