Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

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CD8+ T-cell antigen sensitivity is critical for optimal control of persistent viral infections, including HIV-1. The devastating HIV-1 pandemic may be countered by development of a cytotoxic T lymphocyte based vaccine if qualities associated with protection can be defined at the molecular level. However, the heterogeneity of the total viral-specific CTL response confounds identification of protective correlates and T-cell sensitivity is no exception and remains controversial. To address this issue we reduced the heterogeneity of the HIV-1 CTL response to single units, generating 19 CTL clones that recognise the same HIV-1 derived epitope restricted by HLA B*08. Correlation of functional assays directly with the ability of each clone to control HIV-1 replication in vitro, the “viral suppression assay,” identified antigen sensitivity as a key quality for anti-viral efficacy. Remarkably, four clones from this panel, isolated from one individual, a long-term non-progressor, all used an identical TCR yet had distinct antigen sensitivity and suppressive activity. Two of these clones were characterised in detail, and had distinct cytokine profiles, regulated by epigenetic mechanisms, and differential expression of a group of cell surface receptors with the potential to modulate the signalling threshold to antigen. Expression of the TNFα locus of the high sensitivity clone with “Good” suppression was repressed by DNA methylation. Understanding how CTL qualities required for optimal control of HIV-1 replication differentiate and are then enriched in the total CTL response, and if repression of TNFα contributes to this process, will contribute to rational vaccine design. This is the first evidence that avidity maturation in CD8+ T cells with the same TCR affinity occurs in viral infections in humans as reported in the mouse. This suggests the induction of high sensitivity CTL will be critical for an effective HIV-1 vaccine, but offers hope that this can be achieved even in individuals without protective HLA alleles, by further exploration of peripheral avidity maturation and epigenetic regulation of the HIV-1 specific CD8+ T-cell response.

The study of cancer plays an important role in modern medical science. Over the years, a lot has been learnt about the properties and treatment of cancer cells. Despite the remarkable progress made in understanding the genesis of cancer, the work so far has had very little impact in the clinic especially the design of new and improved drugs. Platinum-based drugs such as cis-diamminedichloroplatinum(II) and its anolgue, carboplatin, are the most effective chemotherapeutic agents used in the treatment of testicular, ovarian, bladder and lung cancers. Nevertheless, the emergence of toxic side-effects compromises its clinical effectiveness. It is generally agreed that most of the toxic effects of platinum-based drugs arise from their lack of selectivity. This thesis reports on the development of new platinum(II) complexes bound to carrier molecules with the hope of obtaining compounds which display the cytotoxic effects only in tumour tissue. In addition, some information is included about what is known about the causes of cancer, how it kills and the current methods of treatment / Doctor of Philosophy (PhD)

For the treatment of cancer, immunotherapy has some inherent advantages over other treatment modalities: disseminated disease can be eradicated due to the systemic nature of immunity, the immune system is effective against a wide range of targets, long-term memory can offer added protection against disease relapse, immunotherapy should be relatively non-toxic, and it can be synergistically combined with other treatment platforms such as radiation and chemotherapy. Type 1 immune responses are thought to be superior for the treatment of cancer and, as the quintessential Th1 polarizing cytokine, interleukin-12 (IL-12) holds much promise; however, optimal therapeutic protocols have yet to be developed and clinical results have fallen short of this promise. The in vivo IL-12 experiments described here highlight a characteristic of cellular therapy that has not previously been appreciated. That is, the effect of cell-mediated cytokine delivery on the immediate microenvironment and how that affects the immune response initiated. This observation has implications for the clinical application of IL-12 therapy but may also prove to be an important consideration when studying other immunostimulants. I have herein developed a novel in vitro assay system that I have used to dissect the cellular responses to IL-12 and to identify the signals that are required for activation of a cluster of differentiation 4 (CD4)+ effector population that affects leukaemia cell clearance both in vitro and in vivo. This work, and the future studies proposed, will expand our understanding of the potential of IL-12 immunotherapy and enhance our ability to manipulate therapeutic conditions to favour the desired response. Moreover, the in vitro assay system offers a method for further characterization of CD4+ effector cells and the development of protocols to initiate their potent anticancer activity.

Thesis (M.S.)--University of Nevada, Reno, 2001. / Includes bibliographical references. Online version available on the World Wide Web.

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